SYNTHESIS AND APPLICATIONS OF 2-QUINOXALINOL SALENS AND THEIR METAL COMPLEXES Except where reference is made to the work of others, the work described in this disseration is my own or was done in collaboration with my advisory committee. This thesis does not include proprietary or classified information. _______________________________ Xianghong Wu Certificate of Approval: _________________________ _________________________ Orlando Acevedo Anne E. V. Gorden, Chair Assistant Professor Assistant Professor Chemistry and Biochemistry Chemistry and Biochemistry _________________________ _________________________ Stewart Schneller Thomas Albrecht-Schmitt Professor Professor Chemistry and Biochemistry Chemistry and Biochemistry _________________________ George T. Flowers Dean Graduate School SYNTHESIS AND APPLICATIONS OF 2-QUINOXALINOL SALENS AND THEIR METAL COMPLEXES Xianghong Wu A Dissertation Submitted to the Graduate Faculty of Auburn University in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Auburn, Alabama December 19 2008 iii SYNTHESIS AND APPLICATIONS OF 2-QUINOXALINOL SALENS AND THEIR METAL COMPLEXES Xianghong Wu Permission is granted to Auburn University to make copies of this thesis at its discretion, upon request of individuals or institutions and at their expense.The author reserves all publication rights. ______________________________ Signature of Author ______________________________ Date of Graduation Reproduced in part with permission from Wu, X.; Gorden, A. E. V. J. Comb. Chem. 2007, 9, 601. Wu, X.; Gorden, A. E. V.; Tonks, S. A.; Vilseck, J. Z. J. Org. Chem. 2007, 72, 8691. Copyright 2008 American Chemical Society. Wu, X.; Gorden, A. E. V. Tetrahedron Lett. 2008, 49, 5200. Wu, X.; Bharara, M. S.; Bray, T. H.; Tate, B. K.; Gorden, A. E. V. Inorg. Chim. Acta. Copyright 2008 Elsevier. iv DISSERTATION ABSTRACT SYNTHESIS AND APPLICATIONS OF 2-QUINOXALINOL SALENS AND THEIR METAL COMPLEXES Xianghong Wu Doctor of Philosophy December 19 2008 (B.S. China Pharmaceutical University, 1999) 170 Typed pages Directed by Anne E. V. Gorden Salen ligands have been of interest to a wide variety of chemists for several reasons. They have been investigated in large part due to their ease of preparation and their ability to form stable metal complexes. Derivatives of 2-quinoxalinol are key intermediates as bioactive agents in agriculture, dyes, and have been key pharmaceutical intermediates. The combination of salen and 2-quinioxalinol, 2- quinioxalinol salens (salqu) are expected to be of use in the development of new catalysts, sensor and pharmaceutical agents. In the first portion of this work, a solution-phase parallel method for the synthesis of salqu ligands was designed and optimized. Simple laboratory techniques with low sensitivity to moisture and air for solution-phase parallel reactions were coupled with convenient workup and purification procedures to give high-purity and good yields for a small v salqu ligands library of 20 compounds. During preparation of this library, it was found that upon reaction with salicylaldehydes, 2-quinoxalinol imines were obtained as byproducts. Diamino-2-quinoxalinols produce 2-quinoxalinol imines regioselectively as the only isomer in good yield. The regioselectivity of this reaction was determined by use of isotopic 15 N labeling experiments. The 2-quinoxalinol imines may then be reacted to yield unsymmetrical substituted salqu ligands. Salqu ligands can be further reacted with different metal salts to form salqu metal complexes. Salqu metal complexes were usually applied as pharmaceutical agents and catalysts for many asymmetric reactions. They can be prepared with simple workup process and are usually stable to both air and moisture condition. These complexes present one option for the extraction of metal ions from wastes or waste streams. To take further advantage of these properties, solid phase catalysts have become popular in organic synthetic methods because of increased ease of workup after reactions. Recently, SPE (solid phase extraction) technology has been well developed for use in many purposes. Based on these, salqu ligands and salqu metal complexes, solid phase salqu ligands and their complexes demonstrate promise in new research fields for their catalytic application. Finally, salqu copper complexes have been found to be a kind of high efficient catalysts for the oxidization of C-H bond of aryl methylene compounds. vi ACKNOWLEDGEMENTS I appreciate my major advisor Dr. Anne E. V. Gorden and my committee members Dr. Orlando Acevedo, Dr. Stewart Schneller, Dr Thomas Albrecht-Schmitt and Dr. Jack DeRuiter for help with my publications, Ph.D dissertation, study, and my life. I appreciate help from Dr. John Gorden, Dr. Travis H. Bray and my lab mates Dr. Mohan S. Bharara, Brandon K. Tate, Stephen A. Tonks and Jonah Z. Vilseck for help with XRD, IR, UV and NMR experiments. I would like to express our appreciation to Dr. Thomas Carrington of Auburn University for his help with atomic absorption (AA), IR and HPLC and to Dr. Mike Walla of the University of South Carolina for mass spectrometry. I would like to express appreciation again to Dr. Orlando Acevedo of Auburn University and the Alabama Supercomputer for assistance with computational methods. I must appreciate my beautiful and considerate wife, Shuhong Guo, who takes care of me and my lovely daughter. It is her support that helps me to work very efficiently and finish my Ph.D early. I still need to appreciate my father, my mother, and my brother for their support of my study. Without their support, I would not be able to go to the USA to pursue my Ph.D. The final person that I would like to thank is my lovely daughter, Sizhe Wu. It is her lovely smiles that help me to relax every day. vii Reference format follows the format of The Journal of Organic Chemistry. Structures are drawn by using Chem. Window 6 th Version. Figures or tables are made by Microsoft Office or Microsoft Excel. Format of figures or tables follows the format of The Journal of Organic Chemistry. Portions of this dissertation are from my published articles (Journal of combinatorial chemistry; The Journal of Organic Chemistry; Tetrahedron Letters and Inorganic Chemistry Acta articles.) viii TABLE OF CONTENTS LIST OF TABLES ............................................................................................................. ix LIST OF FIGURES .............................................................................................................x LIST OF SCHEMES........................................................................................................ xiii CHAPTER 1 INTRODUCTION .........................................................................................1 CHAPTER 2 SYNTHESIS OF SYMMETRIC SALQU LIGANDS LIBRARY .............12 CHAPTER 3 IDENTIFICATION OF 2-QUINOXALINOL IMINE AND SYNTHESIS OF UNSYMMETRIC SALQU LIGANDS ...........................24 CHAPTER 4 2-QUINOXALINOL SALEN METAL COMPLEXES: SYNTHESIS AND CHARACTERIZATION ....................................................................36 CHAPTER 5 APPLICATION 1: METAL EXTRACTIONS WITH SALQU RESINS...62 CHAPTER 6 APPLICATION 2: COPPER SALQU COMPLEXES FOR USE IN CATALYSIS..................................................................................................70 CHAPTER 7 CONCLUSIONS AND FUTURE WORK ..................................................92 CHAPTER 8 EXPERIMENTAL SECTION .....................................................................99 REFERENCES ................................................................................................................141 ix LIST OF TABLES Table 1 Results of diamino-2-quinoxalinol synthesis (6). .................................................16 Table 2 Library of symmetric salqu ligands. .....................................................................20 Table3 Calculation results of intermediate 6. ....................................................................27 Table 4 Preparation of 2-quinoxalinol imines (9ax). .........................................................29 Table 5 Preparation of unsymmetrically substituted salqu ligands (8)..............................32 Table 6 Preparation of copper complexes with symmetric salqu ligands (10xyCu)..........39 Table 7 Preparation of uranyl complexes with symmetric salqu ligands (10xyU). ...........40 Table 8 Preparation of transition metal complexes with symmetric salqu ligands............41 Table 9 Preparation of metal complexes with unsymmetric salqu ligands (11xyMetal) ...42 Table 10 UV-Vis extinction coefficients of metal complexes of ligand 7ad in dichloromethane..............................................................................................48 Table 11 Crystallographic data for salqu uranyl complexes 10aeU, 10aaU, 10beU, 10adU, 10bdU, 10ceU. ...............................................................58 Table 12 Selected interatomic distances (?) and angles (?) for uranyl complexes 10aeU, 10aaU, 10beU, 10cdU, 10bdU and 10adU............................60 Table 13 Optimized conditions for different salquCu catalysts (10xyM)..........................80 Table 14 The aryl methylene compounds tested with salquCu catalysts 10adCu. ............84 x LIST OF FIGURES Figure 1 Salen structure, salenH 2 structure (1, 2) and structures of metal complexs (3).....2 Figure 2 Structure of quinoxaline (4) and 2-quinoxalinol (5)..............................................7 Figure 3 Structures of diamino-2-quinoxalinols (6), salqu ligands (7, 8) and 2-quinoxalinol imines (9).......................................................................................8 Figure 4 Structures of 2-quinoxalinol salen complexes (10, 11) and solid phase 2-quinoxalinol salen and complexes (12, 13). ..................................11 Figure 5 Selected Salicylaldehyde Derivatives (18a-18e).................................................18 Figure 6 Optimized ratios of diamino-2quinoxalinol (6) to salicylaldhyde (18) in the preparation of four symmetric salqu ligands......................................19 Figure 7 1 H-NMR results of intermediate (6a) and 2-quinoxalinol imines (9ae)........................................................................................................25 Figure 8 Solute-solvent energy pair distributions for 7ae, 7bc, 7ca, 7cb and 7db..........................................................................................................34 Figure 9 Titration curve of ligand 7ad by uranyl ion in acetone........................................46 Figure 10 MS with OPLS-AA force field calculated structure of symmetric salqu ligands.....................................................................................49 Figure 11 Crystals grown by the method of vapor phase diffusion. ..................................52 xi Figure 12 Crystals grown by the method of solution phase diffusion. ..............................52 Figure 13 Crystal structures of 10aaU, 10adU, 10aeU, 10bdU, 10beU and 10ceU. .........................................................................................................57 Figure 14 Crystal structures of 10aeU. (Side view)...........................................................57 Figure 15 I: Cu 2+ extraction bar graphs indicating the different molar ratios of 12-1 and 12-2 resin to Cu 2+ extracted. II: Cu 2+ extraction with 12-1 and 12-2 resin with respect to agitation time. (Quantified using atomic absorption.) ...................................67 Figure 16 Cu 2+ recovery with time. (Quantified by atomic absorption.)...........................69 Figure 17 Structures of salen, salph and salqu copper complex catalysts. ........................74 Figure 18 Oxidant optimized for conversion of diphenylmethane into benzophenone. ...................................................................................................74 Figure 19 Catalyst 10adCu ratios optimized for conversion of diphenylmethane into benzophenone.................................................................75 Figure 20 Time effect for conversion of diphenylmethane into benzophenone. ...............75 Figure 21 Oxidant ratios optimized for conversion of diphenylmethane into benzophenone. ............................................................................................76 Figure 22 Solvent effect for conversion of diphenylmethane into benzophenone. ..................................................................................................77 Figure 23 Optimized conditions with copper salt and different salen, salph and salqu metal complexes.......................................................................79 xii Figure 24 The ideal solid phase catalyst structure. ............................................................98 xiii LIST OF SCHEMES Scheme 1 ?- nucleophilic effect seen in diamino-2-quinoxalinol (6). ................................9 Scheme 2 Retrosynthetic analysis of salqu (7 or 8)...........................................................12 Scheme 3 Reaction route for the prepatation of salqu ligands (7 and 8) ...........................14 Scheme 4 Synthetic route for the prepatation of salqu metal complexes (10 and 11).......37 Scheme 5 Reaction route for the prepatation solid phase salqu (12-1 and 12-2). .............64 Scheme 6 Regular and solid phase catalysts for the conversion of diphenylmethane into benzophenone.................................................................90 Scheme 7 Retrosynthetic analysis of salbi ligands (61, 62)...............................................94 Scheme 8 Retrosynthetic analysis of salbi metal complexes (63, 64). ..............................96 1 CHAPTER 1 INTRODUCTION Hugo Schiff, a German chemist (1834-1915), first described Schiff bases and other imines, and was responsible for research into the synthesis and characterization of imines. For this work, the C=N bond named a Schiff base after him. One common type of Schiff base currently of interest is a group called the salen ligands. Salen is the abbreviation for a popular chelating ligand used in coordination chemistry and homogeneous catalysis. The name salen is a contraction for salicylic aldehyde and ethylene diamine, which are the precursors to the ligand. A salen ligand, (Figure 1. 1) in fact, is dianionic with two Schiff bases and two oxo- units forming tetradentate chelating ligand in a coordination complex of the type [O, N, N, O] (Figure 1. 3). The ligand salenH 2 (Figure 1. 2) is a derivative of salen ligand and first was prepared by Pfeiffer. 1 Dr. Eric Jacobsen (Harvard University) and coworkers developed and widened the application of these kinds of ligands and their complexes as organic catalysts and are most famous for using these catalysts for asymmetrically catalyzing reactions with high stereoselectivity. 2 Numerous variations of the simple salen ligand are known with various substituents. For example, ligands abbreviated "Salph" or ?Salqu are derived from the condensation of 1, 2-phenylenediamine or 2-quinoxalinol and salicyaldehyde. 2 R 2 R 2 NN OH HO R 1 R 1(2) R 2 R 2 NN OO R 1 R 1(2) M M = Metal cations 1 2 R 2 N H N H OH HO R 1 R 1(2) R 2 3 Figure 1. Salen Salen structure, salenH 2 structure (1, 2) and structures of metal complexs (3) Salen and the related salophen (abbreviated ?salph?) ligands have been investigated in a variety of applications, because of their ease of preparation and ability to form stable metal complexes. 3 Numerous applications have been proposed in bioinorganic chemistry and medicine. For example, copper (I) complexes have been investigated as anti-tumor agents and have been found to be more bioactive than the currently available metal-based anti-tumor drug cisplatin. 4 Ruthenium salen complexes have been studied as protein kinase inhibitors mimicking organic indolocarbazoles. 5 Salen and salph Mn complexes have also been applied as catalytic scavengers of hydrogen peroxide for cytoprotective agents. 6 Another application investigated with using salen or salph ligands is as metal catalyst supports. Their transition metal complexes (Cr, Al, Ti, Co, Cu, Ni, Fe, Mn, Ru 3 and Zr), have been found to be of great utility in the development of such catalysts and some of these have been used to increase the stereoselectivity of products in a variety of reactions as chiral catalysts. When salen or salph Cr complexes act as catalysts, they can promote the coupling of CO 2 into aziridine to form 5-substituted asymmetric oxazolidinones. 7 Such 5-substituted oxazolidinones act as high potential antibacterial agents and are widely used in the pharmaceutical industry, they also have demonstrated utility in organic synthesis as chiral synthons. 8,9 Many Lewis acid catalysts including Cr salen complexes have been applied for this reactions with high enantioselectivity. 10 Allylation of aldehydes, 11 asymmetric ring opening, 12 and enantioselective aminolytic kinetic resolution (AKR) of epoxides 13 are also catalyzed with high enantioselectivity by Cr salen or salph complexes. Salen or salph Al complexes have been found to catalyze enantioselective Michael addition reactions, an important method for C-C bond construction in organic synthesis. 14 The enantioselective formal hydration of ?, ?-unsaturated imides which was once a challenging problem in organic synthesis has also been successfully accomplished with the aid of salen and salph Al catalysts. 15 Ti salen complexes have been used to catalyze the asymmetric ring opening of epoxides 16 and asymmetric addition of KCN and Ac 2 O to aldehydes to form cyanohydrin esters in good yields and with excellent enantioselectivity. 17 Enantiomerically enriched cyanohydrins are versatile intermediates in organic synthesis and many synthetic approaches towards their synthesis are being pursued based on this research. 18 Ti salen complexes may also efficiently catalyze oxidation of cyclic dithioacetals with high enantioselectivity in the system of urea hydrogen peroxide (UHP). 19 Diol analogs are usually synthesized by dihydroxylation of olefins; 20 however, enantioselective synthesis through carbon- carbon bond formation has not been very successful until the development of 4 enantioselective pinacol coupling of aryl aldehydes catalyzed by Ti salen complexes. This offers an excellent alterative way to synthesize diol analogs. 21 Asymmetric ring opening of epoxides can also be done by using Co salen or salph complexes. 22 In fact, the asymmetric ring opening of epoxides is the most commonly reported reaction catalyzed with various salen or salph metal systems. Different metal salen or salph systems have shown good catalytic effect with high enantioselectivity. 12,16,22 Co salen complexes can also catalyze asymmetric intramolecular cyclopropanation 23 and enantioselective Baeyer-Villiger oxidization reactions, which may convert carbonyl groups into ester groups. 24 The oxidation of alcohols into compounds containing carbonyl functional group is one of the most important fundamental reactions in organic chemistry both in the laboratory and the industrial level. Numerous methods have been developed using a variety of reagents for this purpose, 25 but all of these oxidation methods involve environmental hazardous or expensive oxidants and catalysts. Oxidation of alcohols into carboxylic acids and ketones with hydrogen peroxide and Co salen complexes offers a cleaner and more economical method for use in the pharmaceutical industry. 26 In another example, heteroarenes represent structural units frequently found in a broad range of organic compounds including natural products, pharmaceuticals, dyes. An important modification of these, the arylation of azole heteroarenes, can also be fulfilled with Co salen complexes and iodobenzene as catalysts through C-C forming reactions. 27 The hydrolytic kinetic resolution (HKR) of terminal epoxides 28 and enantioselective cyclopropanation to form asymmetric lactone 29 can be catalyzed by Co salen catalysts as well. Methods for the asymmetric synthesis of ?-amino acids have been actively pursued for a long time, because of applications for not only 5 natural ?-amino acids, but alsoartificial ?-amino acid analogs for use in biochemistry, pharmacy, and organic synthesis. 30,31 Recently, salen and salph Cu complexes have been found to be efficient catalysts for asymmetric syntheses of ?-amino acid and ?,?-disubstituted amino acids. 32 In the C-H oxidation of alkylbenzenes and cyclohexane with hydrogen peroxide, salen Cu complexes were also tested as catalysts. 33 Asymmetric addition of trimethylsilyl cyanide (TMSCN) to carbonyl compounds can be performed using chiral Mn salen catalysts. In this way, chiral cyanohydrins that are useful intermediates for the synthesis of numerous pharmaceuticals intermediates 34 including ?-hydroxy acids, 35 ?-hydroxy aldehydes, 36 ?-hydroxy ketones, 36 and ?-amino acid derivatives 37 and ?-hydroxy amines can be produced. 35, 36 Chiral Mn salen complexes are excellent catalysts for the asymmetric epoxidation of unfunctionalized conjugated cis-olefins. 37,38 Catalytic enantioselective epoxidation is one of the most important processes for the synthesis of chiral epoxides, which can be further converted into many important chiral building blocks via stereoselective ring-opening or functional group transformations. 39 This same reaction may also be catalyzed by Mn salen axially immobilized onto insoluble polymers with high enantioselectivity and yields. 40 Ru salen or salph complexes can selectively catalyze the reaction of aerobic oxidation of alcohols to prepare carbonyls. 41 Asymmetric sulfimidation to form sulfoxide and sulfone which are always key pharmacophores may also be catalyzed using Ru salen complexes. 42 The application of these can overcome the key drawbacks of the Witting reaction, which are lower yields and the requirement of strongly basic conditions, in the olefination of aldehydes. 43,44,45 6 Ni salen complexes have been demonstrated to act as redox catalysts in the reaction of indirect electroreductive cyclization (ERC) to form cycloalkane analogs by the redox of C=N of Ni salen complexes. 46 Fe salen or salph complexes can catalyze the aerobic oxidation of hydrocarbons 48 and cleavage of olefins. 49 Zr salen complexes were used for increasing the enantioselectivity in Baeyer?Villiger oxidations. 50 Because of this, these salen or salph metal catalysts have proven very useful in many different chemistry fields, in particular once incorporated into solid supports, because they can more easily be recovered using simple filtration methods. 40, 51 A new possible application of salen or salph ligands is as scavengers to selectively extract excess metal ions either to increase the ease of using or recycling metal catalysts in combinatorial chemistry or for the recovery or identification of toxic or radioactive environmental contaminants. 52-55 Combining these with solid- phase extraction (SPE) technologies would further provide additional advantages. 56,57 To do this, and to develop new applications with salens, we thought to prepare new ligands with additional modifications to the basic salen system Quinoxaline was first discovered by German chemist Hinsberg in 1880 (Figure 2. 4). Quinoxaline derivatives have been found to have anti-tumor, antibiotic, antifungal bioactivies and have been investigated as receptor inhibitors for N-methyl- D-aspartic acid (NMDA) and as HIV-1 inhibitors. 58 An important derivative, 2- quinoxalinol (Figure 2. 5), is a key intermediate for bioactive agents in agriculture, 59 and have been used in dyes 60 and other pharmaceutical applications. 61 Synthetic methods for both parallel solid phase and solution phase methods of synthesis for 2- quinoxalinol derivatives have been previously reported. 62, 63, 64 7 N N 1 2 3 45 6 7 8 N NOH 4 5 Figure 2. Structure of quinoxaline (4) and 2-quinoxalinol (5). Other compounds containing imine functional groups also have broad applications in organic chemistry. One application of interest is in the preparation of amino acids via a Strecker reaction in bioorganic field. 31 When catalyzed by chiral catalysts, nucleophilic addition to imines is also used for the preparation of compounds possessing secondary amine groups with high stereoselectivity. 65 In medicinal chemistry, imines have been found to have broad bioactivities from anti- tumor to antibacterial bioactivity 66 and to serve as protein synthesis inhibitors. 67 In recent reports, imine coordination ligands supporting copper metal complexes have been demonstrated to trap toxic gases. 68 In addition, imines are useful as protecting groups for amines. 69 Imines can also play a crucial role as coordination ligands in catalyst supports. 70 8 N NOH R 1 N N OH OH R 2 R 2 or R 3 N NOH R 1 N H 2 N OH R 2 N NOH R 1 H 2 N NOH R 2 N NOH R 1 H 2 N H 2 N 1 2 3 45 6 7 8 7, 8 (7: R 1, R 2, R 2 ; 8: R 1, R 2, R 3 ) 9a 9b 6 Figure 3. Structures of diamino-2-quinoxalinols (6), salqu ligands (7, 8) and 2- quinoxalinol imines (9). All of these factors have served to peak our interest in combining these two systems (salen and 2-quinoxalinol) for the preparation of a new series of symmetric and unsymmetric salqu framework ligands based on a Schiff base synthesis. (Figure 3. 7 and 8) [Chapter 2] Previously, no salqu ligands have been reported, perhaps because of the difficulty in preparing the required diamino 2-quinoxalinol intermediate (Figure 3. 6), and the typical Schiff base methods of preparation vary widely or require additional catalysts because of steric constraints. 71, 72 Both problems restrict the development of a synthetic library. In addition, in order to allow for the preparation of unsymmetric salqu ligands, the most challenging thing is the synthesis of 2-quinoxalinol imines (Figure 3. 9), because they are often unstable with side 9 reactions that occur during imine formation. 73 It can be especially difficult to obtain a single isomer as the final product. 74,75 If the reaction can be controlled such that only one amine is reacted with an aldehyde, this would provide a method to prepare unsymmetric salqu ligands (8) [Chapter 3]. A second challenge was in the identification of the exact structure of 2-quinoxalinol imines, because two isomers are possible. (Figure 3. 9a or 9b) [Chapter 3] From the structure of the diamino-2-quinoxalinol (6), it is possible that there is a difference in the reactivity of the amino groups at the 6 position and the 7 position, because of the 2-hydroxy group of diamino-2-quinoxalinol. Therefore, these two amino groups could be reacted with different salicylaldehydes to produce unsymmetric salqu ligands; however, to do this, it is crucial to consider which amino group is more reactive or reacts first with salicylaldehyde. In theory, the 6-amino group should be more reactive than 7-amino group since ?- nucleophile effect caused by both the electron donor 2-hydroxy group and the aromatic 2-quinoxalinol ring system. 76 (Scheme 1) This must be first proven by experiment. It could be proved by both calculation methods 77 and by isotopic labeling such as in a 15 N label method which can differentiate the 6 and 7 amino group [Chapter 3]. From these asymmetrically substituted salqu ligands, SPOS methods could be used to prepare salqu ligands on resins to form solid phase salqu ligands (12). N N R 1 OH H 2 N H 2 N N N R 1 O H 2 N H 2 N 6 6' N C Anti-bonding orbital Bonding orbital Scheme 1. ?- nucleophilic effect seen in diamino-2-quinoxalinol (6) 10 Once the conditions for ligand synthesis are optimized, salqu ligands can be reacted with different metal salts to prepare salqu metal complexes using literature methods. 3 (Figure 4. 10 and 11). For the purpose of recognizing their structural character, it is necessary to develop crystal growing methods for the salqu metal complexes. Accurate structures of salqu metal complexes could also be obtained using small molecule X-ray diffraction (XRD) [Chapter 4]. Solid phase salqu ligands could be further designed and synthesized. (Figure 4. 12) With the solid phase salqu ligands in hand, we could develop applications of solid phase salqu ligands for SPE (solid phase extraction) technology [Chapter 5]. Complexes will be investigated for the application of catalysts and their catalytic mechanism [Chapter 6]. Methods for immobilizing salqu ligands or their complexes onto polymers could then be developed and then their application as catalysts or in SPE technology could be further investigated. Solid phase salqu metal complexes (Figure 4. 13) would be of interest for new solid phase catalysts if salqu metal complexes could be found to possess useful catalytic character. The preparation of these kinds of catalysts will require ligand design, metal complex syntheses, catalyst identification, reaction screenings for a given catalyst and catalyst optimization. All of these need to be considered along with a synthetic application for the new methods described. 11 N NOH R 1 N N O O M R 2 R 2 or R 3 N NOH R 1 N N OH OH R 2 R 2 or R 3 Linker 10 (10: R 1 ,R 2 ,R 2 ; 11: R 1 ,R 2 ,R 3 .) 12 M= metals N NOH R 1 N N O O M R 2 R 2 or R 3 Linker resins M= metals 13 resins Figure 4. Structures of 2-quinoxalinol salen complexes (10, 11) and solid phase 2- quinoxalinol salen and complexes (12, 13) 12 CHAPTER 2 SYNTHESIS OF A SYMMETRIC SALQU LIGANDS LIBRARY F NO 2 F O 2 N F O 2 NN 2 O N R 1 OEt(Me) O H 2 N O 2 NN 2 O N R 1 OEt(Me) O N N R 1 OHH 2 N H 2 NN N R 1 OHN NOH OH H H R 2 (R 3 )R 2 7 and 8 6 Scheme 2. Retrosynthetic analysis of salqu (7 or 8). For the synthesis of a library of functionalized salqu ligands, the ability to incorporate molecular diversity is a key factor during the method design. The method of introduction of diversity sites decides the size of library. 78 From the retrosynthetic route, we determined that we might introduce three sites for diversity one with the amino acid (R 1 ) and two more by using different salicylaldehydes (R 2 and R 3 ) (Scheme 2). There are many different kinds of amino acids available commercially including the 20 most common naturally occurring amino acids and numerous unnatural amino acids. For the salicylaldehydes, there are many different kinds commercially available in addition to the simple salicylaldehyde including multi 13 hydroxy salicylaldehyde or 3, 5-ditertbutyl salicylaldehyde. Therefore, in theory, we can synthesize this three diversity sites salen library in a combinatorial way. Therefore, in theory, we can synthesize this three diversity site salen library using combinatorial methods. There are two ways to do combinatorial synthesis, solution phase parallel synthesis, and solid phase organic synthesis (SPOS). Both methods are potentially useful to us. In this case, solution phase parallel synthesis could be readily used to obtain a library of salqu ligands. 14 N NOH NOH H 2 N R 1 N NOH H 2 N N R 1 OH R 2 R 2 N N R 1 OHH 2 N H 2 N CHO OH R 2 + or N NOH NOH N R 1 OH F NO 2 F O 2 N F O 2 NNO 2 N R 1 OEt(Me) O H 2 N O 2 NNO 2 N R 1 OEt(Me) O a b c a. THF, amino acid 1eq, DIEPA, b. NH 3 .H 2 O ,THF, c. Pd C, HCOONH 4 , EtOH( %), N N R 1 OH 2 N H 2 N H H e f 9a 9b 8 14 15 16 17 18 d g 6 to 18 is 1:10, 48hr. f. MeOH, refluxing, ratio H H R 2 (R 3 )R 2 6 7 7: R 1 , R 2 , R 2 8: R 1 , R 2 , R 3 95 N 2 , d. Air or O 2 . e. MeOH, refluxing, ratio of of 6 to 18 is 1:1.2, 4-14hr. g. MeOH, refluxing, aldehyde 18', 14hr. 3eq Scheme 3. Reaction route for the prepatation of salqu ligands (7 and 8). Previously, Liu and coworkers reported the solution-phase parallel synthesis of a series of diamino-2-quinoxalinol derivatives (e.g., 6). 61-64 Our synthetic route to a combinatorial library of symmetric substituted salqu ligands is shown in Scheme 3. Based on Liu?s previous work, 61-64 our synthesis employs a sequence of four straight forward and high-yielding reaction steps beginning from the commercially available 1,5- 15 difluoro-2,4-dinitrobenzene (DFDNB) and to obtain diamino-2-qnioxalinols (6). We have further simplified and optimized the synthetic methodology for the synthesis of the diamino-2-quinoxalinols (6), a kind of key intermediates. Here, the scavenger resins used in the previous investigations have been replaced by the use of two equivalents of DIPEA (diisopropylethylamine) to remove the acid of HF and HCl on the amino acid methyl group produced in the first step of the reaction sequence. Ammonium hydroxide in water (3 equivalents) was used in the substitution of the second fluorine (Step b, Scheme 3.). In this way, the preparation of the intermediate (16) does not require additional purification after the substitution of the two fluorine atoms, because any water or any remaining unreacted ammonium hydroxide can be removed using high vacuum. This serves to make it easier to prepare these compounds using parallel solution methods as well as reduce the costs of materials. After reduction using 2.5 equivalents 5% wet Pd on carbon and 20 equivalents of ammonium formate, the target intermediates, diamino-2-quinoxalinols (6), are easily recrystallized from 95% ethanol. For the development of a diverse library of these intermediate diamino 2-quinoxalinols (6), different kinds of methyl ester amino acids to be used as the building blocks were selected for the initial library: phenylalanine with an aromatic group, methionine containing a hetero atom (sulfur), alanine, valine and leucine with simple alkyl groups, glycine with neutral hydrogen and the unnatural trifluoromethyl amino acid with a trifluoromethyl electron withdrawing group at R 1 . The purity of each intermediate (6) is over 99.0% and the yields of them are over 90.0% (Table 1.). The sulfur atom in intermediate 6d (made from the methionine starting material) leads to a poisoning of the catalytic palladium on carbon, so the yield of this product is lower than 16 others. When R 1 is hydrogen or the strong electron withdrawing group CF 3 , their diamino 2-quinoxalinols (6e and 6f) are very unstable and decompose quickly. Table 1. Results of diamino-2-quinoxalinol synthesis (6). No. Compound R 1 Purity (%) ? R t (min) Yield (%) * 1 6a 99 3.46 97 2 6b 99 3.53 90 3 6c 99 3.18 99 4 6d S 99 3.47 68 5 6e CF 3 - - - 6 6f H - - - ? Identified by HPLC; R t is retention time. * One step yield of the Pd-C reduction. The available commercial salicylaldehydes chosen to prepare the salqu ligands from intermediates (6) included hydrophilic salicylaldehydes (dihydroxide, 18a and 18b, Figure 5.) and hydrophobic salicylaldehydes (mono- and ditertbutyl, 18c and 18d, Figure 5.) to build our library or salqu ligands (Table 2.). These selections will also later provide a variety of compounds of varying solubility and coordination properties for the continuation of this project in the development of applications. 17 Four different reactions were used in order to optimize the solution phase parallel conditions (Figure 6.). The reaction conditions were optimized by evaluating the effects of varying the reaction times, temperatures, solvents, and reaction ratios of diamino-2- quinoxalinols (6) to substituted salicylaldehyde derivatives (18) on the formation of products. According to previously published preparations of Schiff base compounds in the literature, 71,72 we began using methanol as solvent, with a ratio of 1:2.5 of diamino-2- quinoxalinol (6) to salicylaldehyde derivatives (18) at room temperature. The reaction mixture was allowed to react and stir under nitrogen for 48 hours. Under these conditions, the desired products are not obtained. With heating from room temperature to reflux temperature for 48 hours, the major product is the half-unit ligand 9 which has two possible structures (9a or 9b) and a small amount of the full unit target compound 7cd (20.0%), 43.0% 7ad and 60.0% 7ae. Increasing the reaction time from 48 hours to 72 hours did not result in additional full unit products nor did increasing the reaction temperature benefit the reaction progress. Changing the solvent from methanol to higher boiling point solvents (e.g., toluene, DMF and benzene) allowed for increasing the reflux temperature, but did not produce the desired product. Initially, we resisted increasing the ratio of salicylaldehyde derivatives to diamino-2-quinoxalinol derivatives (6) without efficient scavenging resins to remove the excess salicylaldehyde. Because of this, microwave methods were tried; however, this resulted in the decomposition of the starting materials within a short time demonstrated (6). Sonication was used in another intensive energy method, but again the expected salqu ligands were not generated. 18 OH CHO OH CHO OH HO CHO OH CHO OH 18a 18b 18c CHO OH 18d 18e Figure 5. Selected salicylaldehyde derivatives (18a-18e). On increasing the ratio of intermediates 6 to salicylaldehyde derivatives 18 from 1:2.5 to 1:5 (Figure 6), the yield of full unit target product went up from 20% to 31% for 7cd. The yields of 7ad and 7ae do not change dramatically. On increasing the ratio of to 1:7.5, the yields of target products increased to 52% for 7ad, 44% for 7cd and 60% for 7ae. Fortunately, the final products precipitate from methanol solution. This is a very beneficial phenomenon for solution phase parallel synthesis allowing the use of parallel filtration. 61-64 When the ratio was increased from 1:7.5 to 1:10, the yields of 7cd and 7ae increased to 57% and 77%, but the yields for 7ad did not change significantly. Continuing to increase the ratio to 1:15 does not lead to better results. Target products were filtered directly, resulting in yellow solids. These were washed with 95% ethanol and ice cold acetone five times each. It was determined that there was no final product in 19 the filtered solution using TLC, and the yellow solids are very pure symmetric substituted salqu ligands. These were characterized by 1 H-NMR, 13 C-NMR, MS and HRMS. The purity of 7ad, 7cd and 7ae identified by 1 H-NMR is no less than 99%. For 7da, at the ratio of 1:10 of 6d to 18a, we can not obtain any of the target product 7da, but when we increased the reaction concentration by reducing the volume of solvent of methanol, using a ratio of 1:10, we can obtain 7da in good yield (65%). 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0% Yi e l d ( % ) 1/2.5 1/5.0 1/7.5 1/10.0 Ratio of diamino-2-quinoxalinol to salicylaldhyde 7ad 7cd 7ae 7da Figure 6. Optimized ratios of diamino-2quinoxalinol (6) to salicylaldhyde (18) in the preparation of four symmetric salqu ligands. The final optimized conditions for the synthesis of the symmetric salqu ligands include the ratio of 1:10 of diamino-2-quinoxalinol derivatives (6) to salicylaldehyde 20 derivatives (18) heated to reflux temperature in methanol and allowed to react for 48 hours. When we synthesized this as a 4?5 library, we found that this procedure is very suitable for the solution phase parallel synthesis of symmetric salqu ligands. Results are shown on Table 2. All of these twenty targeted products are synthesized by parallel methods. The yields and purities of the products are very high. Purity of the final products was determined by the proportion of typical peak areas of 1 H-NMR, assuming the half unit Schiff base ligand (9) is the only major byproduct. HPLC can not identify the exact percentage of this major impurity because the large difference of absorbance of their UV (254 or 214nm). Table 2. Library of symmetric salqu ligands. ? One-step yield from diamino 2-qunioxalinol 6 to final salqu ligands 7. No. Product R 1 R 2 Purity (%) Yield (%) ? 1 7aa 3-OH >90 50 2 7ab 5-OH >95 41 3 7ac 3-tert-butyl >95 55 4 7ad 3,5-Di-tert- butyl >99 56 21 5 7ae H >99 77 6 7ba 3-OH >90 64 7 7bb 5-OH >95 44 8 7bc 3-tert-butyl >99 56 9 7bd 3,5-Di-tert- butyl >99 55 10 7be H >90 70 11 7ca 3-OH >95 50 12 7cb 5-OH >90 67 13 7cc 3-tert-butyl >95 52 14 7cd 3,5-Di-tert- butyl >99 57 15 7ce H >99 86 16 7da S 3-OH >90 65 17 7db S 5-OH >90 57 22 18 7dc S 3-tert-butyl >95 46 19 7dd S 3,5-Di-tert- butyl >99 56 20 7de S H >95 81 From these results and optimized conditions, some trends are clear. With each diamino-2-quinoxalinol (6), the yield of the product with aldehyde 18e was significantly higher most likely due to limited steric hindrance, but yields were quite good with using aldehyde 18d or 18c, which should be the most sterically hindered aldehyde. This is also the aldehyde with the best solubility and products from this aldehyde are soluble in chlorinated solvents, whereas some of compounds synthesized from aldehyde 18a and 18b are soluble only in DMF or DMSO. The most likely causes of the inhibition of product formation in reactions with aldehyde 18a and 18b, are hydrogen bonding or an unfavorable electronic effect caused by electron donor 3 or 5 position hydroxyl group on salicylaldehyde 18a and 18b. More positive charge on the carbon of aldehyde group will favor the formation of C=N bond. In summary, an optimized solution phase parallel synthetic method for symmetric substituted salqu library (7) has been developed and by this method a library of 20 symmetric substituted salqu ligands has been obtained with good yields and high purities. Some byproducts, the 2-quinoxalinol imines (9), were obtained at the same time. These byproducts have two possible structures (9a or 9b). In theory, 9a should be the preferred product based on ? - nucleophilic effect, but this requires support with by experiments 23 and/or accurate calculations. Once the structures of 2-quinoxalinol imines (9a) have been identified, a series of unsymmetric substituted salqu ligands could then be prepared. In the next chapter, the methods of confirming the accurate structure of the 2-quinoxalinol imines (9a) will be illustrated, and a developed method for synthesis of unsymmetric substituted salqu ligands will be introduced. 24 CHAPTER 3 IDENTIFICATION OF 2-QUINOXALINOL IMINE AND SYNTHESIS OF UNSYMMETRIC SALQU LIGANDS We have synthesized a library of symmetric substituted salqu ligands. 79 In order to incorporate chiral character into salqu ligands to prepare unsymmetric substituted salqu ligands, the introduction of unsymmetric substitution is necessary. We identified that the ratio of intermediates used diamino 2-quinoxalinols (6) to salicylaldehyde derivatives (18) is crucial to results of the reaction. 79 When the ratio is 1:2.5, a 2-quinoxalinol imine (9) is the major byproduct with high regioselectivity. Continuing to decrease the ratio of intermediates (6) to salicylaldehyde derivatives (18) (1:1.2), 2-quinoxalinol imines (9) are the major products whereas yields of symmetric salqu ligands (7) are very low. The identification of 2-quinoxalinol imines (9) in the reaction is very important to determine the utility of these compounds in unsymmetric syntheses, because two configurations (9a or 9b) are possible. In order to identify the exact structure, we differentiated these two amino groups of diamino 2-quinoxalinol intermediate (6) by replacing ammonium hydroxide with 15 N labeled ammonium hydroxide during the secondary substitution of DFDNB. Because of the heteronuclear coupling of 15 N, 1 H-NMR can be used to demonstrate a difference 25 between the two amino groups of intermediate (6). Thus, in the 2-quinoxalinol imine intermediate (9), the position of the imine formation (whether on the 15 N or 14 N of intermediate 6) can be identified. The simplified 1 H-NMR spectra with intermediate (6a), 2-quinoxalinol imine (9ae) and the 15 N labeled intermediate (6a- 15 N), 2-quinoxalinol imine (9ae- 15 N) are shown in Figure 7. Chemical shift (ppm) 9ae 9ae- 15 N Chemical shift (ppm) 1 2 3 45 6 7 8 6a 6a- 15 N I II III IV 6a 6a- 15 N 9ae N NOH N H 2 N OH N NOH 15 N H 2 N OH 9ae- 15 N (7-amino group) (7-amino group) (6-amino group) (6-amino group) Note: For intermediate (6a), 1 H-NMR of hydrogen of two amino groups has been shown. For 2-quinoxalinol imine (9ae), just the hydrogen on the carbon of imine group has been shown. Figure 7. 1 H-NMR results of intermediate (6a) and 2-quinoxalinol imines (9ae). 26 In Figure 7, for intermediate (6a), the ?a? labeled peaks corresponded to the two protons of the 14 N and 15 N amino groups are different in spectra I and II. In spectra I, it is a broad single peak, while in spectra II, with 15 N heteronulear coupling, the protons are split (J=78.0Hz). For the 15 N labeling 2-quinoxalinol imine (9ae- 15 N), the peak marked ?b? corresponded to the proton on the carbon of imine group are split by 15 N (J=3.0) (spectra IV), whereas it is still a single peak in spectra III. At the same time, in the spectra III and IV, the peak (?=4.66ppm) disappear. Therefore, it is obvious to conclude that the final structure of 2-quinoxalinol imines is 9ae. The reason as to why the 6-amino group is higher reactivity than the 7-amino group can be explained based on either a kinetic or a thermodynamic argument. In the kinetic explanation, 2-quinoxalinol ring is an aromatic system, and 2-hydroxyl group is an electron-donor group which increases electron density of the carbon contacting 6- amino group and so making 6-amino group more reactive than the 7-amino group (an ?- nucleophile effect). This effect is evident in the 1 H-NMR of intermediate 6 (Figure 7). There is a substantial difference between the chemical shift of hydrogen on 6 and 7 amino groups (?? = 0.81ppm, as identified in the labeling study). The two amino groups are in the same benzene ring, the up-field hydrogen of the 6-amino group must have more electron density and, therefore, the 6-amino group is more reactive than the 7-amino group downfield. This can be further confirmed by computational results. The density functional theory method B3LYP/6-31G(d) was used to characterize some intermediates (6) and 2- quinoxalinol imines (9a) and ground states in vacuum using Gaussian 03. 77 Calculations 27 using B3LYP/6-31G(d) were used for geometry optimizations and the calculation of vibrational frequencies, which confirmed all stationary points as minima and provided thermodynamic corrections. The effect of methanol was approximated by subsequent single-point calculations using the conductor-like polarizable continuum model (CPCM). 77 The default Gaussian 03 dielectric constant of 32.63 was used for methanol. Partial charges for the intermediate (6) and 2-quinoxalinol imines (9a) were obtained using CHELPG method. 77 The calculation results show that the 6-nitrogen in each case has more negative charge than the 7-nitrogen. (Table 3) Therefore, 6-amino group of 2- qunioxalinol should be more reactive that 7-amino group. Table 3. Calculation results of intermediate 6. N N R 1 OH H 2 N H 2 N 6 Intermediate R 1 Charge of 6-N (? 6 ) Charge of 7-N (? 7 ) ?? 6-7 6a -0.857 -0.831 0.026 6b -0.856 -0.831 0.025 6c -0.861 -0.839 0.022 6d S -0.848 -0.817 0.039 6e H -0.852 -0.823 0.029 28 Finally, for a justification based on thermodynamics, the minimized energy of three pair of 2-quinoxalinol imine?s isomers (9ad and 9bd, 9af and 9bf and 9ai and 9bi) has been calculated with the same method (vida supra) in the model of gas and methanol. Minimized energy 9ad, 9af and 9ai are lower 0.869, 0.931 and 0.954 in gas model; 0.8, 0.889 and 0.106 Kcal/mol in MeOH model than their respective isomers (9bd, 9bf and 9bi). Therefore, from the thermodynamic view, 9ad, 9af and 9ai are much more stable than their isomers, in other words, the 6-amino group should be higher in reactivity (as measured by decreased potential energy of the isomer) than the 7-amino group isomers. Therefore, based on the identified 2-quinoxalinol imines (9ae), a series of 2-quinoxalinol imines have been prepared (Table 4). The synthetic method for the preparation of 2-quinoxalinol imines (9ax) begins with the addition of 1.0 equivalent of the intermediates (6) dissolved in methanol to a methanol solution of 1.2 equivalents substituted salicylaldehyde derivatives (18). The two are combined with stirring, and after heating at refluxing temperature for 1 hour, the reaction mixture becomes deep yellow or red. Stirring at reflux temperature was continued for 14 hours, and monitored by TLC. Once it is observed that the reaction mixture no longer contains intermediates (6), the reaction is stopped by allowing the mixture to cool to room temperature. Pure 2-quinoxalinol imines (9ax) are obtained by flash column chromatography using hexane : ethyl acetate, 3 : 1 as eluent. According to this method, eight different 2-quinoxalinol imines (9aa-9ah) were prepared. (Table 4) The yield of final products ranges from 65.0% to 94.0%. 29 Table 4. Preparation of 2-quinoxalinol imines (9ax). Product R 1 R 2 Yield (%) 9aa 3-tert-butyl 93.8 * 9ab 3-tert-butyl 70.2 * 9ac 3-tert-butyl 71.5 * 9ad S 3-tert-butyl 65.5 * 9ae 3,5-Di-tert-butyl 76.7 * 9af 3,5-Di-tert-butyl 66.0 * 9ag 3,5-Di-tert-butyl 89.2 * 9ah S 3,5-Di-tert-butyl 80.0 * 9ai 3-OH 68.5 * 9aj H 3-tert-butyl - ? 9ak H 3,5-Di-tert-butyl - ? * This is a one-step yield after purification by column chromatography. ? The major byproducts are 9aj-1 and 9ak-1. 30 N N R 1 OH N H 2 N OH R 2 9ax N NO N N OH OH N NO N N OH OH H H H H 9aj-1 9ak-1 When R 1 is a hydrogen atom, this diamino-2-quinoxalinol (6e) is not stable and was found to decompose on exposure to air. Because of this, it was used directly for the following reaction with 1.2 equivalents salicylaldehyde derivative (18c and 18d) under nitrogen gas protection without purification after the reduction reaction. In fact, it is the hydrogenating diamino 2-quinoxalinol (17) that directly reacts with salicylaldehyde derivatives without regioselectivity. The major byproducts are 9aj-1 (11.0%) and 9ak-1 (10.0%). The expected products 9aj and 9ak may not be obtained. For sample 9ai, a modified procedure was used. After heating to reflux temperature for 4 hours, a red precipitate (9ai) forms. The red solid was filtered off and washed with 95% ethanol followed by ice cold acetone resulting in the pure final 2- quinoxalinol imine (9ai). Unlike the previous reactions, prolonging the reaction time did not increase the yield of product (9ai). Other salicylaldehyde derivatives with different functional groups in the 3 position were tried, but the expected final 2-quinoxalinol imines (e.g., 9a) were not obtained. 31 In contrast, in some cases, low yields of the symmetric substituted salqu ligands (7) were obtained. Presumably due to steric hindrance, we found that primarily when the 3 position has a bulky group such as the tert-butyl group, the 2-quinoxalinol imines (9a) were formed as the major products. The 9ai is a special case, but when another intermediate (6) with different group R 1 is reacted with 2, 3-dihydroxy salicylaldehyde, the expected products are not formed. These results demonstrate that the 2-quinoxalinol aromatic system and 3 position bulky group of salicylaldehyde derivatives are necessary to the regioselective effect. All of the final products were identified and characterized by 1 H-NMR, 13 C-NMR, MS, HR-MS, and IR. Based on these experiments, nine 2-quinoxalinol imines (9aa-9ai), and twelve unsymmetrically substituted salqus ligands (8a-8l) were obtained. (Table 5) The procedure for the synthesis of these unsymmetrical salqu ligands is unique and can be done in one pot. According to the general procedure of synthesis of 2-quinoxalinol imines 9a, when the imines are formed, without additional purification, a second substituted salicylaldehyde derivative (18?) was directly added into the methanol reaction solution. The reaction mixture was allowed to heat to reflux temperature for another 14 hours, and in the end, a precipitate forms. The end product can be filtered and washed with 95% ethanol and ice cold acetone five times each. These precipitates were directly identified by NMR and MS. The purities of them are very high. All of unsymmetrical salqu ligands (8a-8l) are of low solubility in water, hexane, methanol, or ethanol. When R 3 is H, these ligands are very soluble in DMSO or DMF, but not in DCM or CHCl 3 , whereas other unsymmetric salqu ligands are, in contrast, soluble in DCM or CHCl 3 , but of low solubility in DMSO. 32 Combinations of different R 1 , R 2 and R 3 groups were tested. Altering the R 1 group does not appear to affect the reactivity of 6, 7-amino group. When intermediate 6a is reacted with the first salicylaldehyde 18 containing the R 2 group being 3-tert-butyl, R 3 of the second salicylaldehyde 18? added could be H or 3,5-di-tert-butyl and the yield of these unsymmetrical salqu ligands (8a, 8b, 8d, 8e, 8g, 8h, 8j and 8k) are 50.0%~70.0%, whereas when R 2 is a hydroxyl group, there is no expected product; however, when R 2 is 3,5-di-tert-butyl, there is only one combination which has a good yield of these unsymmetrical salqu ligands, that is, R 3 is 3-tert-butyl, the yield is a bit lower (~45%). The reason why these combinations can form and other combinations can not form is not entirely clear yet, but presumably it is due to steric hindrance in the transition state. Table 5. Preparation of unsymmetrically substituted salqu ligands (8). N N R 1 OH N N OH OH R 3 R 2 8 Product R 1 R 2 R 3 Yield (%) * 8a 3-tert-butyl 3,5-Di-tert-butyl 49.1 8b 3-tert-butyl H 60.5 33 8c 3,5-Di-tert-butyl 3-tert-butyl 41.0 8d S 3-tert-butyl 3,5-Di-tert-butyl 54.2 8e S 3-tert-butyl H 63.0 8f S 3,5-Di-tert-butyl 3-tert-butyl 44.7 8g 3-tert-butyl 3,5-Di-tert-butyl 50.0 8h 3-tert-butyl H 68.5 8i 3,5-Di-tert-butyl 3-tert-butyl 38.5 8j 3-tert-butyl 3,5-Di-tert-butyl 50.5 8k 3-tert-butyl H 66.4 8l 3,5-Di-tert-butyl 3-tert-butyl 43.7 * The yield is a two step yield, that is, the yield from diamino-2-quinoxalinol 6 to final products 8. Previously, all of the final imine formation reactions described have been prepared in methanol. 79, 80 Other solvents such as toluene, acetonitrile, THF and DCM were tested in the process of optimization, but these resulted in lower yields or poor 34 results. The success of the 2-Quinoxolinol Salen (or Salqu) ligands synthesized in methanol with high yields could be explained to some extent through the use of calculations of the solute-solvent energy pair distributions in explicit methanol solvent. Monte Carlo (MC) simulations, as implemented in BOSS4.6, 77 was carried out using the OPLS-AA force field. 77 Solute-solvent energy pair distributions record the average number of solvent molecules interacting with the solute. The associated energies are shown in Figure 8. From these calculations, the numbers of solvent molecules (methanol) that contribute to the stabilized salqu ligands through hydrogen bonding interactions are quantified. 0 0.5 1 1.5 2 - 1 1 . 7 5 - 1 0 . 2 5 - 8 . 7 5 - 7 . 2 5 - 5 . 7 5 - 4 . 2 5 - 2 . 7 5 - 1 . 2 5 0 . 2 5 1 . 7 5 3 . 2 5 4 . 7 5 Energy (Kcal/mol) Nu mb er of m et han ol mo le cu les 7db 7cb 7ae 7bc 7ca Figure 8. Solute-solvent energy pair distributions for 7ae, 7bc, 7ca, 7cb and 7db. 35 Hydrogen bonding in methanol is reflected in the left-most region, with energies more attractive than -5 kcal/mol. The large bonds near 0 kcal/mol result from the many distant solvent molecules in outer shells. From Figure 8, there are strong H-bonding interactions occurring between salqu ligands and solvents. Integration of bands from -15 to -5 kcal/mol for 7ae, 7bc, 7ca, 7cb, and 7db, result in three, three, four, four and five methanol molecules. From visual inspection of the solvent environment around salqu ligands, 7ae, 7bc, 7ca, 7cb, and 7db, it appears that three, three, four, four and five methanol molecules are coordinated with the hydroxyl groups of solute, which is in agreement with calculated results. 36 CHAPTER 4 2-QUINOXALINOL SALEN METAL COMPLEXES: SYNTHESIS AND CHARACTERIZATION Once the syntheses of the symmetric and unsymmetric salqu ligands were optimized, we became interested in the preparation of metal complexes. These could have applications as metal complexes for pharmaceutical use, in catalysis or asymmetric reactions, or as colorimetric or fluorescent sensors. Since many different metal salen complexes have been developed for use in catalysis, 8-51 salqu ligands coordinated should also prove useful in this application. Salen ligands usually react easily with +2 metal salts to form salen metal complexes in good yields, +2 metal salts with acetate, sulfate, chloride or nitrate counter ions were selected to react with salqu ligands. Methanol was selected as solvent to dissolve metal salts. If there is a tert-butyl group in salqu ligands, DCM was selected as solvent to dissolve ligands. Otherwise, DMF was used to dissolve ligands. When the two solutions were allowed to mix and react at room temperature, the formation of metal complexes was noted by a change of the reaction solution from bright yellow. If metal salts can not dissolve into methanol, the reactions are usually very slow 37 with very low yields. Most metal acetates have good solubility in methanol whereas metal sulfate and nitrate salts have poor solubility. Therefore, a series of transition metal acetate salts were selected for investigation, including Ni(AcO) 2 , Cu(AcO) 2 , Mn(AcO) 2 , Co(AcO) 2 , Pd(AcO) 2 , Mg(AcO) 2 , Zn(AcO) 2 and the, radioactive actinide UO 2 (AcO) 2 . FeCl 2 which has good solubility in methanol was also selected to test for possible complexation with salqu ligands. The lanthanide salts, Ce (III) acetate and chloride salts and Gd (III) chloride were also tested for coordination with salqu ligands. It was found that Ce, Ga, Mg and Zn cations did not coordinate with salqu ligands even if the temperature was increased to reflux temperature for 24 hours. The application of sonication was also tested with these unreacted metal cations, but salqu ligands were not found to form metal complexes. Other metal cations including uranyl acetate may completely coordinate with salqu ligands to generate corresponding complexes (10 and 11) in very good yields (>80.0%) in less than 2 hours at room temperature. The purities and yields of complexes are very high. (Scheme 4 and Table 6-9) N NOH NOH N R 1 OH 7: R 1 , R 2 , R 2 8: R 1 , R 2 , R 3 R 2 (R 3 )R 2 N NOH NO N R 1 O M R 2 (R 3 )R 2 10: R 1 , R 2 , R 2 11: R 1 , R 2 , R 3 M = Metal M or MO 2 (O=M=O) MeOH/DMF or DCM M(OAc) 2 (1:1) Scheme 4. Synthetic route for the prepatation of salqu metal complexes (10 and 11). 38 Preparation of the salqu metal complexes begins from a DMF or DCM solution of 1 equivalent salqu ligands (7 and 8) were mixed with 1.2 equivalent methanol metal salts solution and stirred at reflux temperature for two hours (with the exception that the uranyl acetate salts are reacted at room temperature). The reaction color changed from bright yellow. The solution was concentrated and washed with 95% EtOH, ether or hexane to obtain salqu metal complexes (10 and 11) with yields from 80.0-98.0% (See table 6 and table 7). These complexes are found to be very stable to air or moisture. Metal cations which can react with salqu ligands under reflux temperature may also coordinate with salqu ligands at room temperature; however, heating reactions with the transition metals to reflux temperature was used to prepare pure complexes by breaking coordination bonds between acetic acid and salqu metal complexes. On the other hand, uranyl metal salqu complexes were found to not coordinate with the acetate as strongly in this case. These also formed single crystals suitable for characterization by small molecular X-ray diffraction (XRD) easily, thus uranyl metal acetate still reacts with salqu ligands at room temperature. From the results of the metal complex preparations presented in tables 6-9, six single crystals of salqu uranyl metal complexes were obtained (marked in the table by the symbol ?). These were characterized using single crystal X-ray diffraction (XRD). None of the transition metal complexes resulted in crystals suitable for characterization by XRD. Uranyl salqu complexes which were marked by symbol ? were characterized using 1 H-NMR, but other metal complexes are paramagnetic, and so this effect limits the utility of NMR technology. MS and HR-MS were run for many of these complexes to confirm 39 their structures, which are marked by?. Complexes were run IR marked by ?. All of complexes which are marked by star were tested as catalysts for different reactions. These will be described in chapter 6. Table 6. Preparation of copper complexes with symmetric salqu ligands (10xyCu). N N R 1 OH N N O O Cu R 2 R 2 10xyCu Entry R 1 R 2 Yield (%) 10aaCu 3-OH 89.0 10adCu ?? 3,5-Di-tert-butyl 82.8 10aeCu ? H 88.0 10beCu * H 87.8 10ceCu * H 91.0 40 Table 7. Preparation of uranyl complexes with symmetric salqu ligands (10xyU). N N R 1 OH N N O O UOO R 2 R 2 10xyU Entry R 1 R 2 Yield (%) 10aaU ? ??? 3-OH 85.9 10abU ? 5-OH 94.0 10acU 3-tert-butyl 86.4 10adU ? ??? 3,5-Di-tert-butyl 80.1 10aeU ? ??? H 80.7 10bdU ? ??? 3,5-Di-tert-butyl 87.5 10beU ? ??? H 97.8 10caU 3-OH 91.0 41 10cbU ? 5-OH 90.5 10cdU 3,5-Di-tert-butyl 91.0 10ceU ? ??? H 88.0 10deU ??? S H 92.2 Table 8. Preparation of transition metal complexes with symmetric salqu ligands. N N R 1 OH N N O O M R 2 R 2 10xyMetal Entry R 1 R 2 M Yield (%) 10aaFe 3-OH Fe 95.0 10adMn ?* 3,5-Di-tert-butyl Mn 96.5 10adCo ??* 3,5-Di-tert-butyl Co 80.0 10adNi ??* 3,5-Di-tert-butyl Ni 92.7 42 10adPd ? 3,5-Di-tert-butyl Pd 92.0 10aeMn * H Mn 91.0 10aeNi H Ni 90.7 10aeCo H Co 94.1 10aePd H Pd 86.0 10aeFe * H Fe 87.4 10bdMn * 3,5-Di-tert-butyl Mn 79.8 10cbCo 5-OH Co 89.7 Table 9. Preparation of metal complexes with unsymmetric salqu ligands (11xyMetal). N N R 1 OH N N O O M R 3 R 2 11xyMetal 43 Entry R 1 R 2 R 3 M Yield (%) 11bMn ?* 3-tert-butyl H Mn 80.0 11bU ? 3-tert-butyl H UO 2 82.0 11dCo * S 3-tert-butyl 3,5-Di-tert- butyl Co 89.7 11eNi * S 3-tert-butyl H Ni 85.3 11eFe S 3-tert-butyl H Fe 81.9 11fCu * S 3,5-Di-tert- butyl 3-tert-butyl Cu 90.0 11iMn * 3,5-Di-tert- butyl 3-tert-butyl Mn 88.4 11jCu * 3-tert-butyl 3,5-Di-tert- butyl Cu 86.2 In the 1 H-NMR spectra of the uranyl (UO 2 2+ ) complexes, a significant shift in the imine CH=N proton is observed in the uranyl metal complexes (9.6-9.8ppm for 10aaU, 10aeU, 10ceU, 10beU and 10deU, 9.1 - 9.3ppm for 10adU and 10bdU) as compared to these free ligands (8.9 - 9.3ppm). (This difference in 10adU and 10bdU is presumably due to the difference in solvation.) This is indicative of the imine nitrogen lone pairs 44 coordinating to the metal center. In a similar fashion, there are three or five hydroxyl peaks in the 1 H-NMR spectra of the free ligands (12.1 ? 13.3 ppm) while in the uranyl (UO 2 2+ ) complexes, two of them are not seen due to coordination of the phenolic oxygens with metal center. In the IR spectra of uranyl complexes 10aeU, 10aaU, and 10adU have strong peaks around 1620 cm -1 (free ligands 1654 - 1658 cm -1 ) indicating coordinated imine nitrogens. 81 The uranyl complexes of ligands 10beU, 10ceU and 10deU have a strong vibration around 1603 cm -1 (free ligand 1658 cm -1 ) indicating coordinated imine nitrogens. This slight difference from 10aeU, 10aaU, and 10adU may be the result of the absence of the phenyl group in the quinoxolinol backbone. Coordination through the phenolic hydroxyl unit in the salicylaldehyde coordination site can also be shown by the shift in the C-O band for uranyl complexes of 10aeU, 10aaU and 10deU (around 1200 cm -1 ) as compared to these free ligands (around 1270 cm -1 , respectively). 82 This is also seen in 10beU and 10adU although it is shifted slightly from the other ligands with bands at 1263 cm -1 and 1229 cm -1 respectively compared to their free ligands (1278 and 1261 cm -1 ). Bands around 900 cm -1 seen in these uranyl complexes are due to the asymmetric and symmetric UO 2 stretching characteristic of linear uranyl ion in the complex. 83 Broad peaks in free ligands seen in the IR spectra around 3400 cm -1 are indicative of the presence of the hydroxyl groups. These are seen for uranyl complexes (around 3400 cm -1 ) but prove to be absent in the transition metal complexes 10adCu, 10adMn, 10adCo and 10adNi, presumably indicating the formation of metal complex with oxygen of 2- hydroxyl of 2-quinoxalinol backbone. This coordination can be confirmed using the shift in the C-O band of the hydroxy unit in the salqu coordination site for the transition metal 45 complexes of 10adCo (1256 cm -1 ), 10adCu (1260 cm -1 ), 10adNi (1260 cm -1 ) and 10adMn (1248 cm -1 ), compared to their free ligand, 7ad (1261 cm -1 ). This is also seen in bands indicative of binding to the lone pairs of the imine nitrogens in the complexes of 10adCo (1614 cm -1 ) and 10adNi (1616 cm -1 ) compared to the free ligand 7ad (1656 cm - 1 ). In DMF, ligand 7ae features two UV peaks at 305nm (?=32000) and 390nm (?=32000). The addition of an aqueous solution of HCl causes (2-fold excess, PH=4) a very slight shift from the peaks at 305nm and 390nm to 300nm and 390nm with no change seen in the extinction coefficients. Upon the addition of the uranyl ion (UO 2 2+ ), as a solution of uranyl acetate, the absorption maximum in the UV-Vis spectra demonstrates a shift to 290nm (?=20000) and 370nm (?=15000) and the formation of an additional peak at 440 nm (?=15000), indicating the formation of uranyl complex. Similar bands have been reported for multidentate hydroxyl-containing uranyl complexes (390 and 450 nm). 84 A similar shift is seen in the spectra of uranyl complex 10beU which features additional peaks with maxima at 287 nm (? = 1.7?10 4 ), 304 nm (? = 1.6?10 4 ), 360 nm (? = 1.3?10 4 ), 385 nm (? = 1.3?10 4 ), and 419 nm (? = 1.4?10 4 ). The 10adU complex in DMF also demonstrated a shift due to the formation of metal complex with maximum absorption at 295 nm (? = 2.5?10 4 ), 375 nm (? =1.6?10 4 ), and 440 nm (? =1.5?10 4 ). When the solvent was changed to acetone, the same ligand (7ad) was titrated with uranyl ion, and UV-Vis data was recorded after each addition of uranyl ion. As the titration proceeded, the absorbance maximum due to the free ligand 7ad at wavelength 390 nm decreased as another maximum formed at 428 nm due to the formation of the uranyl complex, as shown in Figure 9, proceeding from the spectrum labeled A to the 46 one labeled E. It was found to be significantly different than the copper complex of the same ligand in DMF, 10adCu 280 nm (? = 3.4?10 4 ), 325 nm (? =2.8?10 4 ), and 454 nm (? =1.5?10 4 ). 0 0.2 0.4 0.6 0.8 1 1.2 300 350 400 450 500 550 Wavelength (nm) Absorbance A B C D E 428 nm 390 nm Figure 9. Titration curve of ligand 7ad by uranyl ion in acetone. (A is the curve of free ligand 7ad, E is the curve of 10adU complex.). Because of spectral changes due to the effects of solvent and from ligand to ligand, in order to have a better comparison between uranyl and other potentially competing metals, the transition metal complexes of ligand 7ad were prepared along with the uranyl complex in dichloromethane for UV-Vis spectroscopy. The results are shown in table 10. The different metal complexes can be distinguished by their distinct spectra. The differences between the spectra seen in the coordinating solvent DMF and the non- coordinating DCM, are due to the fact that the fifth coordination site in the plane of the 47 uranyl is not filled by solvent, possibly leading to dimers. The cobalt complex has two intense peaks at 322 nm (?=6.0?10 4 ) and 437 nm (?=6.9?10 4 ). The copper complex demonstrated the most intense peaks with the highest extinction coefficients at 330nm (?=7.6?10 4 ) and 458nm (?=9.2?10 4 ) and an additional peak at 286 nm (?=6.2?10 4 ). The manganese complex demonstrated two intense peaks at 372 nm (?=4.0?10 4 ) and 510 nm (?=7.1?10 4 ), and so could be distinguished by the unique peak at 510 nm. The nickel complex had four peaks with one very close to the 458 nm of copper at 452 nm (?=9.1?10 4 ), but could be distinguished from copper by the additional peaks at 388 nm (?=5.7?10 4 ), 314 nm (?=4.8?10 4 ) and 268 nm (?=4.6?10 4 ). Finally, the uranyl in dichloromethane is unique with two shoulders at 379 nm (?=2.4?10 4 ) and 456 nm (?=1.7?10 4 ) resulting from the metal complex and peaks at 250 nm (?=3.4?10 4 ) and 300 nm (?=2.9?10 4 ) from the ?-? * interactions. When salqu ligands were reacted with different metals, it was found that Mg, Zn, Ga and Ce cations do not coordinate with salqu ligands under these conditions although these metal salts totally dissolve into solvent methanol. The configuration and geometry of ligands usually determines their coordination properties. Numerous preparations of transition metal complexes with some salqu ligands were prepared to try to grow for single crystals suitable for diffraction by several different conditions, but no of these resulted in quality single crystals. Therefore, calculation methods have been applied to investigate the configuration and geometry of the salqu ligands and their transition metal complexes for comparison. 48 Table 10. UV-Vis extinction coefficients of metal complexes of ligand 7ad in dichloromethane. Metal Ion (Max Wavelength) Extinction Coefficient Metal Ion (Max Wavelength) Extinction Coefficient Free ligand (301 nm) 44500 Cobalt (437 nm) 69000 Free ligand (391 nm) 44100 Cobalt (322 nm) 60000 Manganese (510 nm) 71000 Copper (458 nm) 92000 Manganese (372 nm) 40000 Copper (330 nm) 76000 Nickel (452 nm) 91000 Copper (286 nm) 62000 Nickel (388 nm) 57000 Uranyl (250 nm) 34000 Nickel (314 nm) 48000 Uranyl (300 nm) 29000 Nickel (268 nm) 46000 Uranyl (379 nm) 24000 Uranyl (456 nm) 17000 To simulate the structure of salqu ligands (7aa, 7cb and 7db) in MeOH, Monte Carlo (MC) simulations, as implemented in BOSS4.6, 77 was carried using the OPLS-AA force field method. 77 The results showed an enlarged coordination cavity caused by twisting structure from a planar configuration. (Figure 11) This can be explained by an electrostatic repulsion of the two phenolic oxygens on the interior of the ligand system, but hydrogen bonding of the lone pair of the imine nitrogen may also contribute. From these calculation results, the NO and NO dihedral angles ? or coordination bite angles - of the salqu cavity coordination were computed. (Figure 10) Their respective dihedral angles (7aa, 7cb and 7db) were determined to be 25.0 o , 34.9 o and 30.3 o . The corresponding distance between the cooridation sites likely produce a cavity suitable for 49 binding transition metal Cu, Mn, Ni, and the larger actinide UO 2 . The atomic radii and preferred coordination bite angle of Zn, and Mg will likely have smaller distance for the cavity of salqu ligands. The lanthanides Ce and Ga are bigger than that of transition metals, but they typically have shorter bond lengths and reduced flexible in term of geometry than that of uranyl. Thus the preferred geometry of uranyl might be described as closer to that of Cu but with longer bond lengths. The calculated results suggest that salqu ligands may be well sorted to bind Cu, Mn, Ni and UO 2 as opposed to the smaller Zn and Mg or bigger Ce and Gd metal cations. Figure 10. MC with OPLS-AA force field calculated structures of symmetric salqu ligands (7aa, 7db and 7cb). To support the calculation results, twist configuration and geometry of salqu ligands, single crystals of salqu uranyl complexes can be easily grown for understanding their real configurations although single crystals of their ligands can not be obtained. Methods for growing crystals of their uranyl complexes have been obtained by solution diffusion and vapor diffusion methods (Figure 11, 12). Crystals of 10aeU?DMF, 50 10aaU?DMF, 10beU?DMF and 10ceU?DMF were grown by solvent diffusion of the uranyl complex in dimethyl formamide with ether. (Figure 11) Uranyl complexes 10adU?H 2 O and 10bdU?H 2 O were prepared to demonstrate a second crystallization method, solution diffusion method, grown from a saturated solution of salqu ligand in acetone layered with a saturated aqueous solution of uranyl acetate. (Figure 12) X-ray diffraction data was collected at -80 ?C on a Bruker SMART APEX CCD X-ray diffractometer unit using Mo K? radiation from crystals mounted in Paratone-N oil on glass fibers. SMART (v 5.624) was used for preliminary determination of cell constants and data collection control. Determination of integrated intensities and global cell refinement were performed with the Bruker SAINT Software package using a narrow-frame integration algorithm. The program suite SHELXTL (v 5.1) was used for space group determination, structure solution, and refinement. 85 Refinement was performed against F 2 by weighted full-matrix least square, and empirical absorption correction (SADABS 86 ) were applied. H atoms were placed at calculated positions using suitable riding models with isotropic displacement parameters derived from their carrier atoms. Crystals of 10aeU?DMF, 10aaU?DMF, 10beU?DMF and 10ceU?DMF formed as dark red acicular prisms, conforming to space group C2/c with Z = 4 or 8. The general coordination motif of uranyl-Schiff base complexes is similar to that seen in the uranyl (UO 2 2+ ) salophen (N,N?-disalicylidene-o-phenylenediaminate) complexes having a pentagonal-bipyramidal geometry with the equatorial plane of the uranyl ion coordinated by the two oxo- and two aza- coordination sites of the ligand and the fifth position in that plane occupied by a DMF solvent molecule. 87 (Figure 13) This was typical with what 51 was seen in this series of ligands. These salqu metal complexes demonstrate a significant twist upon coordination of a metal, which is in accordance with calculation results. This can be seen in the side view of the salqu uranyl complex 10aeU. (Figure 14) This is more pronounced than the 35? seen in the salqu uranyl complex, close to 45? from the coordination plane of the metal ion indicating a strongly bonded complex. The average U-N bond distance in the coordination core is 2.55(3) ?, and the average U-O bond distance is 2.25(5) ?. These bond distances are comparable to the salophen uranyl complexes reported previously. 87 (Figure 13) Single crystals of the uranyl complexes 10adU?H 2 O and 10bdU?H 2 O were prepared using a solution diffusion method. Such a method might be more suitable for modelling or demonstrating possible uses in extraction applications. This serves to demonstrate the strong coordination capability of the ligand specific to the uranyl ion. Crystals formed as red needles at the interface of the two layers, conforming to space group P2 1/ n with Z=4 for 10adU?H 2 O and space group C2/c with Z=8 for 10bdU?H 2 O. The asymmetric unit cell contains two independent, seven-coordinate uranyl complexes that differ in the conformation of the ligand substituents. This results in a noticeable difference in the bond distances despite similar environment around uranium center. (Table 12) Each complex has one ligand coordinating the metal ion and the fifth coordination site occupied by a water or DMF molecule. The U-O bond distances in the ?yl? oxygens are typical for uranyl complexes, averaging 1.78(2) ?. The angles of the O- U-O of the uranyl metal ions are near linear at 177.6(10) for U1 and 178.51(11) for U2. The average bite angle of the N-U-O angle is 68.9(3). The average U-N and U-O bond 52 distances in the coordination core of the two molecules are very similar to that seen before, 2.56(4) ? and 2.25(2) ?, respectively. Crystals of 10aeU?DMF, 10aaU?DMF, 10beU?DMF and 10ceU?DMF (vapor diffusion) Figure 11. Crystals grown by the method of vapor phase diffusion. Crystals of 10adU?H 2 O and 10bdU?H 2 O (solution diffusion) Figure 12. Crystals grown by the method of solution phase diffusion. 53 In summary, a method for preparing salqu metal complexes has been developed. By analysis of their NMR, IR, MS (HRMS) and UV-vis data, strong coordination between the salqu cavity (C=N, O, O, C=N) of salqu ligands and metals has been disclosed. For some small radii transition metals and lanthanide metals Ce and Gd metals, they can not coordinate with salqu ligands, which can be explained by calculation results of configuration and geometry of salqu ligands. These calculation results can be further supported by the interpretation of uranyl salqu complexes single crystal structures. In addition, competing experiments indicate that salqu ligands are more selective to copper cation than nickel and manganese cations, which indicate that if salqu ligands were immobilized onto insoluble polymers, SPE technology can be further developed. 54 10aaU 10ceU 55 10bdU 56 10aeU 10adU 57 10beU Figure 13. Crystal structures of 10aaU, 10adU, 10aeU, 10bdU, 10beU and 10ceU. Figure 14. Crystal structures of 10aeU. (Side view) 58 Table 11. Crystallographic data for salqu uranyl complexes 10aeU, 10aaU, 10beU, 10adU, 10bdU, 10ceU. Compounds 10aeU 10aaU 10beU Empirical formula Fw (g/mol) Wavelength (?) Crystal system Space group Z a (?) b (?) c (?) a (deg) ? (deg) g (deg) V (? 3 ) Density calc?d (g/cm 3 ) Abs coeff (mm -1 ) F(000) Cryst size (mm 3 ) Reflns collected Indep reflns Refinements method GOF of F 2 Final R indices [I>2?(I)] R indices (all data) Largest diff peak and hole (e/ ? 3 ) C 32 H 27 N 5 O 6 U 815.62 0.71073 Monoclinic C2/c 8 33.449(2) 7.404(4) 28.564(1) 90 124.200(1) 90 5851.0(5) 1.852 5.603 3152 0.03x0.1x0.02 28742 7246 [R (int) = 0.0603] Full-matrix Least Squares on F 2 1.025 R 1 = 0.0435 w R 2 = 0.0968 R 1 = 0.0668 w R 2 = 0.1051 2.561 and -0.561 C 32.75 H 28.75 N 5.25 O 8.25 U 865.89 0.71073 Monoclinic C2/c 4 16.403(2) 7.196(4) 28.974(3) 90 93.968(3) 90 3412.0(6) 1.686 4.814 1680 0.02x0.1x0.02 10978 7362 [R (int) = 0.0608] Full-matrix Least Squares on F 2 1.030 R 1 = 0.0746 w R 2 = 0.1967 R 1 = 0.0746 w R 2 = 0.1967 2.845 and -2.384 C 28 H 26 N 5 O 6 U 767.58 0.71073 Monoclinic C2/c 8 26.074(2) ? 7.291(5) ? 28.868(2) ? 90 99.572(1) 90 5411.7(6) 1.882 6.051 2952 0.02x0.1x0.02 17281 6501 [R (int) = 0.0496] Full-matrix Least Squares on F 2 0.950 R 1 = 0.0388 w R 2 = 0.0863 R 1 = 0.0684 w R 2 = 0.1036 2.074 and - 1.089 59 Compounds 10adU 10bdU 10ceU Empirical formula Fw (g/mol) Wavelength (?) Crystal system Space group Z a (?) b (?) c (?) a (deg) ? (deg) g (deg) V (? 3 ) Density calc?d (g/cm 3 ) Abs coeff (mm -1 ) F(000) Cryst size (mm 3 ) Reflns collected Indep reflns Refinements method GOF of F 2 Final R indices [I>2?(I)] R indices (all data) Largest diff peak and hole (e/ ? 3 ) C 108 H 146 N 8 O 19 U 2 2336.39 0.71073 Monoclinic P2 1 /n 4 21.084(2) 23.115(2) 23.334(2) 90 107.461(1). 90 10848(1) 1.431 3.050 4744 0.4 x 0.02 x 0.25 94464 26956 [R (int) = 0.0513] Full-matrix Least Squares on F 2 0.950 R 1 = 0.0333 w R 2 = 0.0789 R 1 = 0.0517 w R 2 = 0.0848 1.766 and -0.876 C 95.50 H 113 N 8 O 16.5 0 U 22336.39 2099.06 0.71073 Monoclinic C2/c 8 56.825(5) 14.2963(13) 33.170(3) 90 107.461(1). 90 23188(4) 1.211 2.845 8464 0.3 x 0.3 x 0.1 64823 16800 [R (int) = 0.0567] Full-matrixLeast Squares on F 2 1.026 R 1 = 0.0407 w R 2 = 0.1246 R 1 = 0.0565 w R 2 = 0.1339 1.448 and -0.572 C 29 H 28 N 5 O 6 U 780.59 0.71073 Monoclinic C2/c 8 27.907(4) 7.2573(10) 28.949(4) 90 107.420(3). 90 5594.2(13) 1.854 5.855 3061 0.25 x 0.07 x 0.07 12158 4005 [R (int) = 0.0775] Full-matrix Least Squares on F 2 1.005 R 1 = 0.0469 w R 2 = 0.1031 R 1 = 0.0743 w R 2 = 0.1295 1.559 and -1.186 60 Table 12. Selected interatomic distances (?) and angles (?) for uranyl complexes 10aeU, 10aaU, 10beU, 10cdU, 10bdU and 10adU. 10aeU U1-O1 2.241(4) O1-U1-N1 70.57(2) U1-O2 2.250(4) O2-U1-N2 69.38(1) U1-O3 2.400(4) O4-U1-O5 176.71(2) U1-N1 2.521(4) N1-U1-N2 62.83(1) U1-N2 2.582(4) O1-U1-O4 93.03(2) U1-O4 1.782(4) O2-U1-O4 92.37(2) U1-O5 1.796(4) 10aaU U1-O3 2.233(8) O3-U1-N1 70.1(3) U1-O4 2.239(9) O4-U1-N2 71.3(3) U1-O101 2.415(9) O1-U1-O2 176.71(2) U1-N1 2.571(10) N1-U1-N2 63.6(3) U1-N2 2.528(9) O2-U1-O3 93.0(4) U1-O1 1.800(9) O2-U1-O4 92.9(4) U1-O2 1.786(8) 10beU U1-O1 2.252(4) O1-U1-N1 69.96(2) U1-O2 2.259(4) O2-U1-N2 69.75(2) U1-O5 2.375(5) O4-U1-O3 176.15(2) U1-N1 2.549(5) N1-U1-N2 63.28(2) U1-N2 2.571(4) O1-U1-O3 87.57(2) U1-O3 1.805(4) O2-U1-O3 86.76(2) 61 U1-O4 1.782(4) 10adU U1-O3 2.254(2) O3-U1-N1 69.23(9) U1-O4 2.255(2) O4-U1-N2 68.71(8) U1-O5 2.456(2) O1-U1-O2 177.62(10) U1-N1 2.551(3) N1-U1-N2 63.54(8) U1-N2 2.577(3) O1-U1-O4 91.67(9) U1-O1 1.774(2) O2-U1-O4 87.38(10) U1-O2 1.779(2) 10bdU U1-O3 2.241(5) O3-U1-N1 69.77(18) U1-O4 2.455(5) O4-U1-N2 70.06(17) U1-O6 2.510(6) O1-U1-O2 177.20(2) U1-N1 2.504(6) N1-U1-N2 63.71(17) U1-N2 2.524(6) O1-U1-O4 92.00(2) U1-O1 1.779(5) O2-U1-O4 88.10(2) U1-O2 1.780(5) 10ceU U1-O1 2.277(7) O2-U1-N3 70.20(3) U1-O2 2.262(8) O1-U1-N4 69.30(3) U1-O(1D) 2.386(8) O4-U1-O(1D) 175.80(3) U1-N3 2.539(9) N3-U1-N4 63.10(3) U1-N4 2.631(8) O2-U1-O(1D) 78.40(3) U1-O3 1.794(7) O1-U1-O(1D) 80.30(3) U1-O4 1.779(7) 62 CHAPTER 5 APPLICATION 1: METAL EXTRACTIONS WITH SALQU RESINS (SALQU LIGANDS INCORPORATED INTO FUNCTIONALIZED RESINS FOR SELECTIVE SOLID-PHASE EXTRACTION OF COPPER (II)) In our previous research, both symmetric and unsymmetric 2-quinoxalinol salen ligands have been prepared (See structure 7cb as an example). 79, 80 It has been found that these ligands can strongly coordinate +2 metal cations. 88 This made us consider the possibilities of incorporating these salqu ligands into solid phase resins (12) for use in applications. In this chapter, we will detail the methods of preparing solid phase reagents (e.g., 12), and their application in the selective extraction and recovery of copper cations. N NOH N N OH OH OH OH 7cb 1 2 3 45 6 7 8 1' 2' 3' 4' 5' 6' 63 Polystyrene (PS) aminomethyl resin was selected as solid carrier, because this resin can swell in many organic solvents. Glutaric anhydride was selected as linker between solid carrier and salqu ligands. Isopropyl-salqu ligand (7cb) was selected as the coordination ligand, both because the 5?-hydroxyl group on the outer portion of the salqu is a convenient site for incorporating the resin, and because its yield is the highest of the symmetric salqu ligand library. 79 Presented in Scheme 5 is the optimized method for the synthesis of solid reagents 12-1 and 12-2. Different molar ratios and various solvents were investigated to optimize the acylation of the amino group onto the (PS) aminomethyl resin. Finally, a molar ratio of glutaric anhydride to (PS) aminomethyl resin 5:1 using dichloromethane (DCM) as solvent at room temperature for 24 hours was found to be the optimum conditions for acylation of the amino group. After acylation was completed, the resin was washed with DCM, DMF and MeOH, three times each. The loaded resin PL can be further acylated with 1.5 equivalent of ligand 7cb by using 2.2 equivalents 4-dimethyl-aminopyridine (DMAP) and 2.2 equivalents N,N?-diisopropyl-carbodiimide (DIC) in distilled, dry N,N?- dimethylformamide (DMF) at room temperature for three days. Extending the reaction time does not increase loading. Without DMAP, the loading is very low. If wet DMF was used, the loading capability is decreased, because DIC can be decomposed easily by moisture. 64 N NOH N N OH OH OH OH 7cb NH 2 PS Aminomethyl resins OOO NH OH O O NH O O N NOH N N OH OH OH O NH O O N N OHN N OH OH OH O or a b Reaction conditions: a. 5equiv Glutaric anhydride, DCM, r.t., 24hr. b. 2.2equiv DMAP, 2.2equiv DIC, 1-2equiv 7cd, DMF, r.t., 72hr. PL 12-1 12-2 NH O O N NOH N N O O OH Cu O NH O O N N OHN N O O OH Cu O or c d 13-1Cu 13-2Cu c. Cu 2+ , DCM, MeOH, r.t., 30min. d. NaBH(OAc) 3 , DCM, AcOH, r.t., 4hr. Cu 2+ Cu 2+ Scheme 5. Reaction route for the prepatation solid phase salqu (12-1 and 12-2). 65 There are three potential binding sites (2, 2? and 5? positions) for the carboxylic acid linker to attach to ligand 7cb. Positions 2 and 2?cannot react with the carboxylic acid moiety due to reactive inertia of 2 position and steric hindrance of the 2? position. Hydrogen bonding also limits the reactivity of the hydroxyl group on the 2? position. 74 Reaction with hydroxyl groups in the two 5? positions, results in two possible products (i.e., 12-1 and 12-2). They have the same coordination capability to bind +2 valence metal cations because the salen coordination cavity is not affected by their position. By this procedure, PL was obtained with 100.0% loading by ninhydrin test and solid phase salqu ligands 12-1 and 12-2 were obtained with 60.0-65.0% loading, as determined by mass. Identification of solid phase salqu ligands 12-1 and 12-2 was made by comparing the major peaks of an IR spectra of ligand 7cb (3381.2, 1658.8, 1622.3, 1577.8, 1489.1, 1278.8 cm -1 .). With these solid ligand functionalized reagents (12-1 and 12-2) in hand, extraction studies were run in several different solvent combinations: DMF, DMF/MeOH, MeOH, THF/MeOH, DCM/MeOH and DCM/EtOH. Finally, we found DCM/MeOH is the best combination for our extraction experiments, because the DCM can best swell the PS resins while MeOH still readily dissolves the metal salts. Metal salts of Cu 2+ , Mn 2+ , and Ni 2+ were used in extraction studies. Solutions containing these metal cations were prepared using copper acetate, manganese acetate, and nickel nitrate salts in a 50:50 solution of DCM/MeOH. To determine extraction capability, 3ml of a prepared solution of 2?10 -4 mol/L Cu 2+ was mixed with 5mg, 10mg, 15mg, 20mg prepared 12-1 and 12-2 (The molar ratios of Cu 2+ to 12-1 and 12-2 are 1:3, 1:6, 1:9, 1:12) respectively at room temperature for 66 stirring 40min. The extraction results for Cu 2+ metal solution are shown in (Figure 15. I). It was found that 20mg 12-1 and 12-2 resins may completely extract 3ml Cu 2+ 2?10 -4 mol/L solution at 40min. Further optimization of extraction time using 20mg 12-1 and 12-2 resins with 3 ml 2?10 -4 mol/L concentration copper (II) cations solution at room temperature (Figure 15. II) indicated that the shortest time for 100% extraction is 30 minutes. Complexed Cu resin (13-1Cu and 13-2Cu) can be directly filtered off to separate from the organic solvent. For nickel, 20mg of prepared 12-1 and 12-2 was mixed with 3ml of the nickel (II) (2?10 -4 mol/L) salt solution at room temperature. After 24 hours, only 30% of nickel cations was extracted, and after 72 hours, only 45.7% of the nickel cations was extracted. (The final metal ion concentrations were determined using atomic absorption.) For Mn, the Mn (II) salt solution must be prepared as a 1?10 -4 mol/L solution, because the detection limit for Mn cations by atomic absorption using a hollow cathode lamp is limited. A 3ml 1?10 -4 mol/L manganese salt solution was extracted at room temperature by 10mg 12-1 and 12-2 resins for 24 hours. It was found that 63.0% of the manganese cations was removed by the resin. 67 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 Ex tr act io n rat e (%) 36912 Molar ratio of resins 12-1 and 12-2 to Cu 2+ cations I 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 Extraction precentage (%) 5 15304560 Time (min) II Figure 15. I: Cu 2+ extraction bar graphs indicating the different molar ratios of 12-1 and 12-2 resin to Cu 2+ extracted. II: Cu 2+ extraction with 12-1 and 12-2 resin with respect to agitation time. (Quantified using atomic absorption.) 68 This leads us to a surprising conclusion. 12-1 and 12-2 resins might selectively extract Cu 2+ within a short time (30min). To confirm this, we combined 3ml 2?10 -4 mol/L Cu 2+ and 3ml 2?10 -4 mol/L Ni 2+ solution to prepare a 6 ml 1?10 -4 mol/L Cu 2+ and Ni 2+ mixed solution; 3ml 2?10 -4 mol/L Cu 2+ solution and 3ml 1?10 -4 mol/L Mn 2+ solution were combined to obtain a 6ml 1?10 -4 mol/L Cu 2+ and 5?10 -5 mol/L Mn 2+ solution. To these mixed solutions, 20mg of the prepared 12-1 and 12-2 resins was added at room temperature and allowed to extract for 45min. After filtering off the 12-1 and 12- 2 resins, the extraction solution were analyzed by atomic absorption. It was found that 80.0% of the Cu 2+ was removed, but only 7.8% Ni 2+ in the Cu 2+ /Ni 2+ solution, and only 22.0% Mn 2+ was extracted in the Cu 2+ /Mn 2+ mixed solutions. For the recovery of copper from the 13-1Cu and 13-2Cu resins, several different conditions were tried (Scheme 5). Routine cleavage or recovery conditions, DCM with different organic acids including trifluoroacetic acid were not found to release copper ions, nor were strong bases. Because sodium triacetoxyborohydride can efficiently reduce the imine group (C=N) to amino group (C-N) which coordinates only weakly with the metal, the 20mg 12-1 and 12-2 resins were mixed with 3ml DCM/CH 3 COOH (2:1). To this, 10mg sodium triacetoxyborohydride was added, and the reaction progress was measured over time (Figure 16). 89 The results show that after 4 hours the maximum amount of Cu 2+ can be recovered (70.0%). Extending the reaction time or increasing the amount of sodium triacetoxyborohydride does not increase this recovery rate. 69 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 Re cov er y pe rc en ta ge ( %) 1491836 Time (hours) Figure 16. Cu 2+ recovery with time. (Quantified using atomic absorption.) Thus, an optimized synthetic route for resins PLG1 and PLG2 has been obtained. It has been found that this kind of resin can selectively extract copper (II) cations in a short amount of time. The copper can then be recovered using simple reducing conditions from the resin. This has the potential to enable the selective extraction of copper even from a mixture containing other metals. PLG1 and PLG2 resins could also be applied in environmental or materials chemistry to remove copper or in combinatorial chemistry as a metal scavenging agent to remove excess copper. In the future, we will design new solid reagents to selectively extract other metals and to continue to improve on the selectivity or application of this system. 70 CHAPTER 6 APPLICATION 2: COPPER SALQU COMPLEXES FOR USE IN CATALYSIS The development of new metal catalysts has long been investigated for specialized synthetic applications; 90 however, the application of these in the pharmaceutical industry has been limited for many reasons. Commonly used laboratory catalysts can be difficult or costly to synthesize on a large scale, they are often sensitive to moisture or oxygen, and they often use potentially environmentally hazardous metals such as palladium or ruthenium. Developing less-expensive, easier to use, or more environmentally friendly catalysts is a promising trend for new synthetic methods. 91 Because salen metal complexes can catalyze many reactions, most notably used in chiral reactions, some of these reactions were tested by our salqu metal complexes. The easy to prepare salen metal (Mn, Ru, Co, Cu, etc.) complexes have been used in the development of catalysts for numerous reactions, 92 among these the oxidation of activated C-H bonds; however, this reaction has some limitations because of the low solubility of salen ligands and low yields. 33 Converting C-H bonds of organic molecules directly into the desired organic functional group can potentially offer benefits for organic synthesis because of increased resource efficiency, energy efficiency, and 71 operational simplicity, while at the same time reducing the environmental impacts of wastes. 93 For these reasons, we were interested in developing our salqu metal complexes to be used in catalytic oxidation of activated C-H bonds. Oxidation of C-H of an aryl methylene to form an aryl carbonyl group or aryl ?- hydroxyl group has been well studied in recent years, because of the numerous potential applications. 94 To date, many methods have been developed depending on the application and the required selectivity. In the 1970?s, for this kind of oxidation, the oxidant researchers most commonly uwas sed Se 2 O; however, the mechanism of selenium dioxide oxidation involved the formation of ?-ketoseleninic acids as intermediates, and this lead to the numerous potential side products and low yields. 95 Manganese salts or nitropyridinium salts as oxidants were found to use a hydrogen transfer and radical mechanism, and usually results in yields of no more than 60%. 96 Singlet oxygen has also been used as an oxidant. This process also involves a radical mechanism, and so a mixture of ?-keto and ?-hydroxyl group products is often obtained. 97 More recently, oxidations with hypervalent iodine, 98 tert-butylhydroperoxide, 99 Jones reagent, DDQ and peroxyacid 100 have been explored. Yields all of these methods are less than 80%, and they require rigorous conditions which can limit their use in industrial applications. For this kind of oxidation, catalysts are required for acceleration of the reaction or improvement of yields. Catalysts used in this way have been copper, cobalt, 101 or ruthenium salts. 102 Salen ligands used as manganese or copper catalyst supports have also been used. 103 One recent technique developed is the Gif system, in which an iron catalyst is combined with a suitable carboxylic acid, pyridine, and zinc dust (as a reductant) with oxygen as the oxidant, for the oxidation to acylate methylene. 104 In this 72 reaction, less than 40% yields limit industrial development of the Gif system. 104,105 Many articles reported high conversion rates of this oxidation which were determined by GC or HPLC technology. It is important to note, that this is not a good reflection of their isolable yields, because of different absorptions between starting materials and products, especially for this oxidation which converts an aryl methylene group into aryl carbonyl group would inherently exhibit a stronger UV absorption. Until now, for this particular oxidation, it has been difficult to identify a metal catalyst which has both good solubility in organic polar aprotic solvents (e.g., CH 3 CN) and non polar solvents (e.g., hexane), which could be another bottleneck to the oxidation of non polar compounds like steroids. Based on our library of 2-quinoxalinol salen ligands (salqu), we have developed a new copper catalyst, 10adCu which has good solubility in most organic solvents (Figure 17). Catalyst 10adCu can be easily prepared and can convert aryl methylene groups into aryl carbonyl groups with very high yields under mild conditions. In this chapter, we introduce the optimized process, describe selectivity, and proposed potential applications of salquCu catalyst 10adCu. The conversion of diphenylmethane (19) into benzophenone (20) was selected to test salquCu catalyst 10adCu and optimize conditions. Based on previous reports with salphCu, 33 we began using the addition of 3 equivalents H 2 O 2 , in CH 3 CN as solvent with 1% by molar of the salquCu catalyst 10adCu, heated to reflux temperature for 18 hours. Under this condition, the isolated yield of benzophenone is only 27.0%. Six experimental factors were considered to optimizing this reaction: oxidant (Figure 18), catalyst ratio (Figure 19), time (Figure 20), oxidant ratio (Figure 21), solvents (Figure 22) and types of catalyst (Figure 23 and Table 13). Four oxidants, first, were tested with CH 3 CN as 73 solvent, 1% catalyst 10adCu at reflux temperature for 18 hours. (Figure 18) It was found that tert-butylhydroperoxide in decane was the best oxidant, quantitatively converting diphenylmethane into benzophenone. If tert-butylhydroperoxide in water was used as oxidant, the yield of the desired product, benzophenone, is around 80%. (Figure 18) The reason why tert-butylhydroperoxide in decane is better than in water is that a uniform solvent system is used during this oxidation. Using tert-butylhydroperoxide in decane as oxidant, the catalyst ratio was increased from 0.1% to 3%. (Their turnover numbers are 736, 176, 99 and 32 respectively.) It was found that 1% of catalyst 10adCu is best for this oxidation. (Figure 19) Although 0.1% catalyst 10adCu leads to highest turnover number which is most suitable to industrial use, 1% catalyst 10adCu results in quantitatively conversion which is best for further optimization and reduces the need for separations. The addition of more catalyst does not decrease the amount of time that it takes to achieve the optimal yield and using less catalyst resulted in reduced yields. (Figure 19) Reducing the reaction time or decreasing the oxidant ratio also results in lower yields. (Figure 20 and 21) The addition of more of the tert-butylhydroperoxide oxidant also does not serve to decrease the reaction time required to achieve the optimal yield. 74 N N O O Cu Regular Salph Cu Complex (3Cu) N N N N O O M OH M = Cu (10adCu), Mn (10adMn), Ni (10adNi), Co (10adCo), UO 2 (10adU). Regular Salen Mn Complex (3Mn) N N O O MnCl Figure 17. Structures of salen, salph and salqu copper complex catalysts. 0 10 20 30 40 50 60 70 80 90 100 Yield (%) H2O2 CH3CO3H tBuOOH(decane) tBuOOH (water) Oxidiant Figure 18. Oxidant optimized for conversion of diphenylmethane into benzophenone. Yields are based on purification by flash column chromatography and mass calculation. 75 0 10 20 30 40 50 60 70 80 90 100 Yield (%) 0.1 0.5 1 3 Catalyst 10adCu ratio (%) Figure 19. Catalyst 10adCu ratios optimized for conversion of diphenylmethane into benzophenone. Yields are based on purification by flash column chromatography and mass calculation. 0 10 20 30 40 50 60 70 80 90 100 Yield (%) 13918 Time (hour) Figure 20. The effects of time on conversion of diphenylmethane into benzophenone. 76 0 10 20 30 40 50 60 70 80 90 100 Yield (%) 1234 Oxidant ratio, tBuOOH in decane (equiv.) Figure 21. Oxidant ratios optimized for conversion of diphenylmethane into benzophenone. Yields are based on purification by flash column chromatography and mass calculation. Finally, several polar and non polar solvents were tested. With acetonitrile, chloroform, toluene and hexane as solvents, the yields of the desired product, benzophenone, are very high (over 95%), but using THF as solvent, the yields are very low, because of the degradation of THF under oxidative conditions (Figure 22). 106 It is worth mentioning that when toluene was used as the solvent, there were not any byproducts generated by reaction of the toluene obtained. (This makes sense if we assume that the catalyst procedes through a radical reaction, because a reaction with toluene with produce a primary radical.) Therefore, the optimal reaction conditions are to use acetonitrile as the solvent, (although toluene, hexane or chloroform are also suitable 77 solvents) and include 3 equivalents of tert-butylhydroperoxide in decane as oxidant, with 1% of the catalyst 10adCu heated to reflux temperature for 18 hours. 0 10 20 30 40 50 60 70 80 90 100 Yield (%) Hexane CH3CN CH3Cl Toluene Solvent Figure 22. Solvent effect for conversion of diphenylmethane into benzophenone. Yields are based on purification by flash column chromatography and mass calculation. In chapters 2 and 3, we described the preparation of a library of salqu ligands. 79, 80 These have been demonstrated to form stable complexes of broad solubility with many metal salts (Ni 2+ , Co 2+ , Cu 2+ , Mn 2+ or UO 2 2+ ). 88 Different metal complexes were tested as catalysts. (Figure 23) Without the addition of catalyst, the oxidation using 3 equivalents of tert-butylhydroperoxide in decane as oxidant in acetonitrile heated to reflux temperature for 18 hours, resulted in only a very modest yield, 5-10% of the desired product, benzophenone, was obtained. With the addition of copper salts such as copper sulfate or copper chloride, 50-60% benzophenone was obtained. Using a regular salph Cu 78 complex 3Cu as catalyst further enhances yields to 73.6%, still less than that of catalyst 10adCu, whereas salen Mn complex 3Mn gave almost same yield (74.7%) as that of regular salph Cu complex 3Cu. The reason why catalysts 3Cu and 3Mn give lower yields than catalyst 10adCu remains unclear, but two possibilities come to mind. First, the salqu metal complexes (10adMetal) have different configuration from complexes 3Cu and 3Mn, and they have good solubility in numerous organic solvents. 88 Either possibility might affect the mechanism, which would lead to improved yields. This improved solubility of catalyst 10adCu also allows for the ability to eliminate the need for a biphasic system which would be very useful in increasing the ease of use in larger scale applications. 0 10 20 30 40 50 60 70 80 90 100 Yi e l d (% ) N / A C u ( O A c ) 2 C u C l 2 C u ( S O 4 ) 2 1 0 a d C u 1 0 a d Mn 1 0 a d N i 1 0 a d C o 1 0 a d U 3 C u 3 M n Catalyst type 79 N N O O Cu Regular Salph Cu Complex (3Cu) N N N N O O M OH M = Cu (10adCu), Mn (10adMn), Ni (10adNi), Co (10adCo), UO 2 (10adU). Regular Salen Mn Complex (3Mn) N N O O MnCl Figure 23. Optimized conditions for catalyzed conversion of diphenylmethane into benzophenone.with copper salt and different salen, salph, or salqu metal complexes. As a demonstration of the importance of solubility toward the efficacy of this reaction, different salqu copper complexes from our library were selected for catalytic studies. These results are depicted in Table 13. Besides catalyst 10adCu, tert-butyl functionalized copper complexes 10acCu and 10cdCu show good catalytic effect, whereas hydroxyl functionalized complexes 10bbCu, 10daCu and 10cbCu lead to similar yields as regular manganese salen and copper salph complexes 3Cu and 3Mn. It is also possible that the extra hydroxyl group impairs the catalytic function of Cu or Mn, leading to the lower yields. Complexes 10ceCu and 10beCu gave lower yields than catalysts 10adCu, 10acCu and 10cdCu, because of the reduced solubility. 80 Table 13. Optimized conditions for different salquCu catalysts (10xyMetal). N N N N O O Cu OH R 1 R 2 R 2 O Catalyst 10xyMetal Catalysts 10xyMetal, CH 3 CN, reflux t-BuOOH in decane 18hr 19 20 No. R 1 R 2 Yield (%) * 10adCu CH 2 Ph 3,5-ditertbutyl 99.0 10acCu CH 2 Ph 3-tert-butyl 92.8 10cdCu CH 2 CH(CH 3 ) 2 3,5-ditertbutyl 99.0 10ceCu CH 2 CH(CH 3 ) 2 H 90.4 10cbCu CH 2 CH(CH 3 ) 2 5-OH 80.4 10becu CH(CH 3 ) 2 H 90.3 10bbCu CH(CH 3 ) 2 5-OH 65.0 10daCu CH 2 CH 2 SCH 3 3-OH 77.0 * Yields are based on separation by flash column chromatography and mass calculation. 81 Stability is also an important character of the salqu copper catalysts. Catalysts that are found to be stable both to air and moisture are much more convenient for us in applications. Our catalyst (10adCu) is stable to air and moisture and can be reactivated at least twice. The potential capability for recycling of our catalysts was tested using the optimized reaction condition to oxidize diphenylmethane. Diphenylmethane was reacted with 1% catalyst 10adCu and 3 equivalents tert-butylhydroperoxide in acetonitrile heated to reflux temperature for 18 hours. After 18 hours, another equivalent of starting material, diphenylmethane and an additional 3 equivalents of the oxidant, tert-butylhydroperoxide in decane, were added into reaction system. This was allowed to continue heating at reflux temperature for another 18 hours. This addition was repeated for a third addition the same as the second.. Finally, pure benzophenone was obtained by flash column separation and the total yield for all three additions is over 98.0%. This indicated that the catalyst 10adCu can be recycled or reused at least twice, as there was no loss in yield between additions. This suggests that the catalyst can be reused several times, and the ability to continue this without the addition of catalyst, can be used to reduce the cost of the reaction as dependent on the amount of copper catalyst as well as the volumes of volatile organic solvents required in large scale reactions. Once the optimal conditions were determined, these were used in reactions with several compounds containing aryl methylene group to be oxidized. (Table 14) It was found that if there is an electron donor group neighboring to the methylene group to be oxidized, the yield is increased (Entry 1, 2 and 3. 20, 22 and 24), whereas a neighboring electron withdrawing group will decrease the yield (Entry 4, 5. 26 and 28). An aryl 82 methylene with an electron withdrawing group neighboring can be oxidized a second time to enhance the final yields (Table 2, Method 2). Aryl methylene groups can be selectively oxidized, whereas other methylene groups are not affected (Entry 6. 30). If an amino or hydroxyl group is present neighboring the methylene group, the final product produced is an aldehyde (Entry 2 and Entry 9. 22 and 36). By this method, not only may the aryl methylene be oxidized to carbonyl group, but an ether group can be converted to an ester in good yield (Entry 3. 24). If there is no aryl group neighboring the methylene group, the expected product is not found (Entry 16). This could also be due to a limitation of configurational geometry of the mechanism as when there is a bulky group tert-butyl group on the methylene, there is also none of the expected product (Entry 13). If a halogen is directly neighboring to the aryl methylene, there is also none of the expected product (Entry 14). Compounds containing a hydroxyl group were found to have no reaction (Entry 15) or lower yields (Entry 9. 36), presumably because the oxygen atom could coordinate with the catalyst metal center, (in this case copper), and thus block the catalyst mechanism. Remarkably, tetra-hydroisoquinoline and tetra-hydroquinoline were special cases. Oxidation of these using this method leads to isoquinoline and quinoline (Entry 17 and 18. 53 and 55), but not the ?-ketoisoquinoline or ?-ketoquinoline analogs. For some of the oxidation reactions found to have poor yields, the final yields can be improved using a modified reaction scheme, method 2. (Entry 4, 5, 10 and 11) Also of interest, the oxidation of benzylamine directly into benzaldehyde by the salqu copper catalyst 10adCu mimics the important biological processes of oxidation of amine substrates to aldehydes as catalyzed by the naturally occurring copper containing 83 amyl and lysyl oxidases (Entry 2). 107 Because of the benzaldehyde generated, the benzaldehyde may directly react with unreacted benzylamine to form N- benzylidenebenzylamine, which is an unexplored method to prepare N- benzylidenebenzylamine solely from just cheap benzylamine as compared to established methods. 108 N-benzylidenebenzylamine is a useful, costly but commercially available, indicator reagent used for organolithium assays and as an intermediate of amino acid syntheses. 109 In another example of the potential utility of this catalyst, 1, 4-naphthoquinone is typically prepared from naphthalene using oxygen gas with a vanadium catalyst at high temperature and pressure with yield no more than 40%. 110 This is a key intermediate of several natural products including phylloquinone and menaquinone (vitamin K 1 and K 2 ), 111 the derivatives of which have been found to have broad bioactivity ranging from anticancer to antifungal bioactivity. 112 Several new methods for preparing 1, 4- naphthoquinone derivatives have been developed, but all of them involve more expensive and environmentally hazardous metal catalysts. 113 Here, we set up a new method for preparing 1, 4-naphthoquinone by using inexpensive commercial available starting material 1, 2, 3, 4-tetrahydronaphthalene and easily prepared salquCu catalysts 10adCu with 62.5% yield. (Entry 10. 39) This conversion also mimics another crucial biological oxidized process catalyzed by galactose oxidase. 114 84 Table 14. The aryl methylene compounds tested with salquCu catalysts 10adCu. Entry Starting material Final product Yield (%) * 1 19 O 20 99.0 1 2 NH 2 21 H O 22 88.8 1? 3 O 23 O O 24 93.0 1 4 O 2 N 25 O 2 N O 26 50.0 1 ; 89.9 2 85 5 COOEt 27 COOEt O 28 14.0 1 ; 82.0 2 6 29 O 30 80.0 1 7 31 O 32 81.1 1 8 33 O 34 80.2 1 9 OH 35 H O 36 47.1 1 86 10 37 O 38 O O 39 25.7 2 65.5 2 11 40 O 41 60.0 1 ; 91.1 2 12 N H O 42 N H OO 43 - ? 13 44 O 45 - ? 87 14 Br 46 Br O 47 - ? 15 HO 48 HO O 49 - ? 16 50 O 51 - ? 17 NH 52 N 53 55.5 1 18 N H 54 N 55 66.0 1 * Yields are based on separation by flash column chromatography. 88 ? There is no expected final product obtained. 1 Method 1: 1% catalyst 10adCu, CH 3 CN, 3 equivalents t-BuOOH (in decane), reflux for 18 hours. 2 Method 2: (1) 1% catalyst 10adCu, CH 3 CN, 3 equivalents t-BuOOH (in decane), reflux for 18 hours. (2) 3 equivalents t-BuOOH (in decane), CH 3 CN, reflux for 18 hours. ? After 40 minutes the Schiff base product, N-benzylidenebenzylamine is formed. 88.8% of benzaldehyde was determined by adding the reacted benzaldehyde with pure isolated benzaldehyde. It remains to determine the specific oxidation mechanism. This is difficult, because if the mechanism involves a carbon cation or anion and leaving group mechanism, the methoxyl group should be a better leaving group than hydrogen (Entry 3) in the conversion of the phenyl methyl ether to methyl benzoate. In contrast, we find that in this case, the hydrogen is a ?leaving group?. Secondly, in the conversion of 1,1- diphenylproane to benzophenone and tetra-hydroquinoline to quinoline, the expected products 1, 1-diphenylproanol and ?-ketoquinoline have not been obtained, which indicate an unexpected mechanism occur. (Entry 7 and 53 or 55) Another case which is intricate to this mechanism is benzylamine. (Entry 2) The expected product should be benzoic amide, but benzaldehyde in very good yield is found to be the major product. According to the procedure mentioned in the chapter 5, the solid phase resins functionalized with the copper salqu complexes (13-1Cu and 13-2Cu) were prepared and tested as solid phase catalysts to catalyze the inserted oxidization of aryl C-H bond of 89 diphenylmethane to benzophenone. (Scheme 6) Compared to solution phase salqu copper catalysts (10adCu), solid phase salqu copper catalyst (13-1Cu and 13-2Cu) show lower catalytic effect (their yield is 77.7%); however, when compared to its corresponding solution phase salqu copper catalyst (10cbCu), they show almost same catalytic effect (10cbCu?s yield is 80.4%). Until now, no solid phase catalysts to oxidize this kind of reaction with good yields have been developed. Solid phase catalysts have the potential to simplify work up of reactions to a large extent, although its catalytic yield is a little lower than that of solution phase catalyst 10adCu. In conclusion, a new kind of solution phase salqu copper catalyst 10adCu and solid phase salqu copper catalysts 13-1Cu and 13-2Cu have been developed for selective oxidization of aryl C-H to aryl carbonyl group with high yields. The optimized process indicates that the configuration and solubility of salqu copper complex catalyst (e.g., 10adCu) are key factors during the process of oxidization. Besides salqu copper complex 10adCu, the salqu manganese complex 10adMn also shows catalytic ability. 90 NH O O N NOH N N O O OH Cu O NH O O N N OHN N O O OH Cu O or 13-1Cu 13-2Cu OH N N OHN N O O OH Cu 10cbCu (Yield: 80.4%) Solution phase salqu copper catalysts 10cbCu, 10adCu. Soild phase salqu copper catalysts: 13-1Cu and 13-2Cu. N N OHN N O O Cu 10adCu (Yield: 99.0%) Catalysts O 13-1Cu and 13-2Cu (Yield: 77.7%) 19 20 Scheme 6. Regular and solid phase catalysts for the conversion of diphenylmethane into benzophenone. 91 Using the copper catalyst 10adCu, an important fragment of natural compound, 1, 4-naphthoquinone, can be easily obtained in high yields and two kinds of oxidases, the oxidations of amine oxidase and galactose oxidase, can be mimicked. These types of catalysts present a new option for use in industry or organic synthesis because of their relative ease of preparation, low sensitivity to moisture and air, their use of more environmentally friendly metals, and their solubility in most solvents. They possess high catalytic efficiency and can be recycled at least twice. In future, the mechanism of this oxidization and new reactions catalyzed by our salqu metal complexes will be further investigated. New solid phase salqu copper catalyst will be designed to improve the catalytic yield by immobilizing salqu copper complex 10adCu onto insoluble polymers. 92 CHAPTER 7 CONCLUSIONS AND FUTURE WORK A symmetric salqu library (7) has been prepared and optimized using a simple and efficient solution phase parallel method. It was found that these organic salqu ligands are stable at high temperature (<200 o C) and not sensitive to oxygen, water, alkaline conditions or most solvents. In this optimized process, the synthetic method for the key intermediate diamino-2-quinoxalinol (6) has been further optimized and simplified from methods used in previous reports. Further investigations are ongoing with computational analyses to identify and characterize the transition states in the final step of the Schiff base formation and the limits to the product formation in the ligand systems that result in decreased final yields. Also included in later work will be investigations to determine bioactivity of these compounds. During the synthesis of the symmetric salqu library, some 2-quinoxalinol imines (9a) were obtained as byproducts. We have identified the exact structure of 2- quinoxalinol imines (9a) using isotope 15 N labeled compounds and NMR technology. Based on this, we have successfully developed a series of new compounds, 2- quinoxalinol imines (9a), and we have used these to generate a series of unsymmetrical salqu ligands (8). With the imine functional group in these compounds, we will continue with the development of artificial amino acids and labeled peptides, as well as secondary 93 amine products for screening for bioactivity. With the unsymmetrical salqu ligands in hand, many different metal salqu complexes have been obtained for application as catalysts or bioactivity screening. We have begun to explore ways to develop complexes as potential new chiral catalysts. Based on the optimized method for synthesis of salqu ligands, a benzimidazole salen library (salbi) could also be developed by the similar way using the same starting material (DFDNB) and steps. Benzimidazole analogs not only have broad bioactivity, 115 but also have found applications in pesticides, 116 as a neurotropic reagents, 117 and in agricultural science. 118 (Scheme 7. 59-62) Starting from DFDNB, it could be first substituted by primary amine and then secondary substituted by ammonium hydroxide to obtain the diamino dinitro benzene analog (57). After reduction of diamino dinitro benzene analog (57), an unstable intermediates (58) will be obtained. 64 Because the secondary amino group of intermediates 58 should be more reactive than other three primary amino groups, it could first form benzimidazole ring to obtain key intermediate diamino benzimidazole (59) if equivalent ratio of aldehyde and intermediate 58 would be allowed to react. Because the secondary amino group of the diamino benzimidazole 59 is a strong electron donor group whereas the imine group is the electron withdrawing group, the two amino groups of 59 should have different reactivity. Therefore, an symmetric and an unsymmetric benzimidazole salen (salbi) library (61, 62) could be developed. Overall, there are four diversity sites in the salbi library (R 1 to R 4 ). By adjusting different R groups, the properties of salbi ligands could be controlled for different purposes. 94 F NO 2 F O 2 N F O 2 NN 2 O N R 1 H 2 N O 2 NN 2 O N R 1 H H (R 4 )R 3 R 3 N NOH OH N N R 2 R 1 H 2 N H 2 N N N R 2 R 1 H 2 N H 2 NN 2 H N R 1 H 1456 57 58 59 60 R 3 N H 2 N OH N N R 2 R 1 62 R 3 R 3 N NOH OH N N R 2 R 1 61 Scheme 7. Retrosynthetic analysis of salbi ligands (61, 62). Salqu uranyl-complexes have been synthesized and characterized. Crystal structures demonstrate a typical pentagonal bipyramidal geometry around the uranium center with the 2 aza and 2 oxo coordinating sites of the ligand perpendicular to the ?-yl? oxygens. The remaining coordination site of the metal is occupied by a solvent molecule. A significant twist of salqu from planar is seen to occur upon coordination of a metal. This results in a change in the orbital overlap of the ligand backbone and makes contribution to a dramatic change in the ultraviolet-visible spectrum. 95 The presence of different substitutes on the salicylaldehyde moiety incorporated into the ligand backbone affects the solubility of the ligand greatly and also affects the response seen through spectroscopy. Combining oxo- and imine aza-coordination sites as used here, has been demonstrated to impart a degree of selectivity for uranyl in particular over lanthanides. The ligands have also been found to form stable complexes with Cu, Ni, Co, Fe, Pd and Mn cations with the addition of heat or base. The change in the UV-Vis spectra of the uranyl complex as compared to transition metal complexes, and a preference for uranyl cations, may be exploited in the development of sensors for actinides on surfaces or in contaminated areas. Additional experiments to develop these ligands as selective metal coordination systems for use in sensors or extraction applications will continue with experiments to quantify selectivity for uranium or actinides over lanthanides and with experiments probing fluorimetric methods to increase sensitivity. The use of fluorimetry would be another way to rule out competition from transition metals in sensing of actinides. These investigations will broaden our understanding of the chemical behavior of the actinides and enable the development of new sensors and sensing materials for improved detection and isolation of actinides from fuel wastes or contaminated environmental sites. Based on the proposed synthetic route for salbi (Scheme 8. 61, 62), a new series of salbi metal complexes (63, 64) could be developed for many purposes including new sensors, bioactivity, agriculture and catalysts. (Scheme 8) 96 (R 4 )R 3 R 3 N NO O N N R 2 R 1 M 64 R 3 R 3 N NO O N N R 2 R 1 M 63 or (R 4 )R 3 R 3 N NOH OH N N R 2 R 1 62 R 3 R 3 N NOH OH N N R 2 R 1 61 or Scheme 8. Retrosynthetic analysis of salbi metal complexes (63, 64). An optimized synthetic route for solid phase salqu ligands (12-1 and 12-2) was obtained. This kind of resin can selectively extract copper (II) cations within 30 minutes. The copper cations can then be recovered using simple reducing conditions from the resin. This has the potential to enable the selective extraction of copper even from a mixture containing other metals. Resins (12-1 and 12-2) could also be applied in environmental or materials chemistry to remove copper cations or in combinatorial chemistry as a metal 97 scavenging agent to remove excess copper cations. In the future, designing new solid reagents to selectively extract other metals or improvement on the selectivity of (12-1 and 12-2) will be investigated. A new kind of catalyst, 10adCu and its analogs, which are quite efficient for insertion oxygen into C-H bond of aryl methylene group were developed. The optimized process indicates that solubility and configuration of catalysts 10adCu are key factors during the process of oxidization of aryl C-H bond and salqu manganese complex 10adMn also shows excellent catalytic ability for this oxidization. Using the catalyst 10adCu, an important fragment of natural compound, 1, 4- naphthoquinone, can be easily obtained with high yield and two kinds of oxidases, the oxidations of amine oxidase and galactose oxidase, can be mimicked. The solid phase catalysts 13-1Cu and 13-2Cu have been proved to be efficient for insertion oxygen into aryl C-H bond; however, the solid phase versions, catalysts 13-1Cu and 13-2Cu, result in lower yields than the solution phase catalyst 10adCu. In the future, preparing the immobilized 10adCu incorporated into insoluble polymers (Figure 24. 65) is major step toward improving the catalytic ability of solid phase catalysts, but finding a suitable anchor point is difficult, because the 2-hydroxyl in the of 2-quinoxalinol ring is very unreactive. In addition, the mechanism of this oxidization and new reactions catalyzed by our salqu metal complexes will be investigated. 98 N N N N O O Cu O Linker part 65 1 2 3 45 6 7 8 Figure 24. The ideal solid phase catalyst structure. To sum up, symmetric and unsymmetric salqu ligands have been successfully developed. Their many metal complexes have been synthesized and their uranyl crystals have been obtained and characterized using X-ray diffraction. Two applications of salqu ligands have been explored. The first is the incorporation into SPE technology. Based on the successful immobilization of the salqu ligand, solid phase salqu ligands were found to selectively extract copper (II) within very short time. In a second application, the copper complexes of the salqu were tested as C-H activation catalysts for the oxidization of aryl C-H bond. An important fragment of natural compound, 1, 4-naphthoquinone, can be easily obtained by using our salqu copper catalyst. In addition, solid phase salqu copper catalysts have been developed with appealing catalytic characteristics. 99 CHAPTER 8 EXPERIMENTAL SECTION Synthesis All amino acid methyl esters, DFDNB, HCl (37%), aldehydes, and starting materials for catalytic oxidization were purchased from Acros. Ammonium hydroxide (5.0 N), tert-butylhydroperoxide in decane, palladium on carbon (wet, 5%) were purchased from Aldrich. Starting materials were used as received. Polystyrene (PS) aminomethyl resins (1%DVB, 0.59mol/g loading and 100-200 mesh.) were from ChemPep Inc. The 15 N labeled ammonium hydroxide was purchased from Cambridge Isotope laboratories, Inc. The parallel synthesis was carried out on a Corning parallel synthesizer. All organic solvents were purchased from Fisher Scientific and were directly used for synthesis. HPLC analysis was performed on a Shimadzu apparatus equipped with a SPD- 10A VP detector. Solutions for HPLC were eluted as 50/50 acetonitrile/H 2 O with a buffer consisting of 0.05% TFA over 10 min at 1 mL/min with detection by UV at 254 nm. The column employed was a water C 18 column (w33471F, 3.9?300 mm) from DIKMA. All melting points were recorded on a Mel-temp II melting point apparatus, and the values were uncorrected. The known 1 H and 13 CNMR data of commercial available compounds 100 are available from spectral database for organic compounds (SDBS), National Institute of Advanced Industrial Science and Technology (AIST), Japan. Spectroscopy 1 H and 13 C NMR spectra were recorded on Bruker AC 250 spectrometer (operated at 250 and 62.5 MHz, respectively) or a Bruker AV 400 spectrometer (operated at 400 and 100 MHz, respectively). Chemical shifts are reported as ? values (ppm). Some 1 H- NMR data were collected using DMSO-d 6 and CDCl 3 to dissolve samples because they were not completely soluble only in DMSO-d 6 ; however, if just CDCl 3 is used, the active protons do not appear in D 2 O/water exchange experiments. Reaction progress was monitored by thin-layer chromatography (TLC) using 0.25 mm Whatman Aluminum silica gel 60-F254 precoated plates with visualization by irradiation with a Mineralight UVGL-25 lamp. Electrospray ionization mass spectrometry was performed on a Micromass QTOF mass spectrometer (Waters Corp, Milford MA). Direct probe samples were on a VG-70S mass spectrometer (Waters Corp, Milford MA). All UV data was collected using a Cary 50 UV-Vis spectrophotometer with a xenon lamp and an equipment range from 200 to 1250nm. Atomic absorption spectrum (VarianAA240), its software (AA240FS) and hollow cathode lamp (HLC; Ni 232.0nm, optimum working range: 0.1-20 mg/L; Mn 279.5nm, optimum working range: 0.02- 5mg/L; Cu 324.8nm, optimum working range: 0.03-10mg/L) are from Varian Inc. IR spectroscopic data was collected using a SHIMSDZU Inc. IR, Prestige-21 Fourier Transform Infrared Spectrophotometer and KBr solid samples. Circular Dichroism (CD) spectra were collected using a Jasco J-810 spectropolarimeter. 101 Crystallography X-ray diffraction data for 10aeU, 10aaU, 10beU, 10adU, 10bdU and 10ceU were collected at -80 ?C on a Bruker SMART APEX CCD X-ray diffractometer unit using Mo K? radiation from crystals mounted in Paratone-N oil on glass fibers. SMART (v 5.624) was used for preliminary determination of cell constants and data collection control. Determination of integrated intensities and global cell refinement were performed with the Bruker SAINT Software package using a narrow-frame integration algorithm. The program suite SHELXTL (v 5.1) was used for space group determination, structure solution, and refinement. Refinement was performed against F2 by weighted full-matrix least square, and empirical absorption correction (SADABS43) were applied. H atoms were placed at calculated positions using suitable riding models with isotropic displacement parameters derived from their carrier atoms. Crystal data, selected bond distances and angles, are provided in Tables 7 and 8. Crystallography data for structural analysis of uranyl complexes of compounds 10aeU, 10aaU, 10beU and 10adU have been deposited with the Cambridge Crystallographic Data Center as CCDC nos. 650168, 673941, 673940 and 650169, respectively. General Procedure Synthesis of intermediates (6), diamino-2-quinoxalinols. (Scheme 2, Chapter 2) To a stirring solution of 150 mL of THF, 1.0 equivalent (10.0 mmol, 2.041g) of 1, 5-difluoro-2, 4-dinitrobenzene (DFDNB), 2.2 equivalents (22 mmol, 2.838g) of 102 diisopropylethylamine (DIPEA), and 1.0 equivalent methyl amino acid (10 mmol) were added. The reaction mixture was stirred continuously for 12 hours at room temperature. After it was confirmed by TLC that the starting materials (DFDNB) had been consumed, 3 equivalents (30 mmol, 6ml) of ammonium hydroxide in water was added as 5.0N in aqueous solution to the reaction mixture. The reaction solution is stirred at room temperature for an additional 5 hours until the reaction was determined to be complete, and this was confirmed by TLC. The reaction solution was concentrated to dryness using a rotary evaporator. The resulting product is a yellow oil or oily solid. The resultant yellow oil was dissolved in 100 mL of ethanol (95%) with stirring. To this, HCOONH 4, 20 equivalents (0.2 mol, 12.620g) and 5% wet Pd-C (3.1 g, 7.0g for ligands prepared from amino acids containing sulfur) were added under a protective N 2 atmosphere. The reaction mixture was heated to reflux temperature for 15- 30 minutes. During this time, the reaction mixture changed from the initial yellow to red and, finally, to fluorescent yellow. After this time, the catalyst Pd-C and unreacted HCOONH 4 were filtered from the solution. The filtrate was put into the freezer (0 o C) for 48-72 hours. Yellow crystals were found to form. If there are no solids that precipitate from the solution, using an ultrasonic bath for sonication of the sample can help precipitate the diamino 2-quinoxalinols (6) as a solid. Filtration of the solid from the reaction solution results in highly pure intermediate (6). The totally synthetic yields of 6a-d are 97%, 90%, 99% and 68% respectively. (Table 1, Chapter 2) After drying on high vacuum, HPLC, 1 H-NMR and 13 C-NMR show the purity of each of these are not less than 98%. 103 15 N labeled diamino-2-quinoxalinol (6a- 15 N) 15 N labeled diamino-2-quinoxalinol (6a- 15 N) was synthesized in the same fashion as 6a but secondary substituted by 15 N labeled ammonium hydroxide. 6a 1 H-NMR (400 MHz DMSO-d 6 ): ? 3.99 (s, 2H), 4.66 (bs, 2H), 5.47 (bs, 2H), 6.37 (s, 1H), 6.80 (s, 1H), 7.16-7.31 (m, 5H), 11.86 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 155.1, 152.2, 140.5, 139.4, 133.0, 129.4, 128.6, 126.4, 125.8, 111.0, 96.8, 38.8. Formula: C 15 H 14 N 4 O. MS (M+H): 267.0. HRMS: found (267.1256), calc (267.1246). IR: 3172.9 cm -1 (bs), 3381.2 cm -1 (bs), 3182.6 cm -1 (bs), 3005.2 cm -1 ,1645.3 cm -1 , 1510.3 cm -1 , 1402.3 cm -1 , 1278.8 cm -1 . UV: 402.9nm (bs). mp: 261.4-263.5 o C. 6a- 15 N 1 H-NMR (400 MHz DMSO-d 6 ): ? 3.99 (s, 2H), 4.57 (bs, 1H), 4.76 (bs, 1H), 5.47 (bs, 2H), 6.37 (s, 1H), 6.80 (s, 1H), 7.16-7.31 (m, 5H), 11.86 (bs, 1H). 6b 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.13 (d, J=6.8, 6H), 3.33 (sept, 1H), 4.66 (bs, 2H), 5.36 (bs, 2H), 6.33 (s, 1H), 6.78 (s, 1H), 11.73 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 157.7, 154.7, 140.1, 132.8, 125.9, 125.5, 111.3, 96.9, 29.7, 21.0. Formula: C 11 H 14 N 4 O. MS (M+H): 219.0. HRMS: found (219.1248), calc (219.1246). IR: 3381.2 cm -1 (bs), 3365.1 cm -1 (bs), 2962.7 cm -1 , 2929.9 cm -1 ,1656.9 cm -1 , 1512.2 cm -1 , 1406.1 cm -1 , 1273.0 cm -1 . UV: 394.0nm (bs). mp: 234.5-236.5 o C. 104 6c 1 H-NMR (250 MHz DMSO-d 6 ): ? 0.90 (d, J=6.7, 6H), 2.15 (m, 1H), 2.50 (d, 2H), 4.62 (bs, 2H), 5.39 (bs, 2H), 6.35 (s, 1H), 6.79(s, 1H), 11.98 (bs, 1H). 13 C-NMR (62.5 MHz, DMSO-d 6 ): ? 155.4, 153.2, 140.1, 132.8, 126.0, 125.8, 111.2, 96.9, 41.7, 26.9, 23.0. Formula: C 12 H 16 N 4 O. MS (M+H): 233.0. HRMS: found (233.1410), calc (233.1402). IR: 3352.3 cm -1 (bs), 3277.1 cm -1 (bs), 2949.2 cm -1 , 2868.2 cm -1 , 2818.0 cm -1 , 1653.0 cm -1 , 1512.2 cm -1 , 1419.6 cm -1 , 1402.3 cm -1 , 1271.1 cm -1 . UV: 410.6nm (bs), 299.1 (wbs). mp: 249.5-250.3 o C. 6d 1 H-NMR (400 MHz DMSO-d 6 ): ? 2.09 (s, 3H), 2.83 (t, 2H), 2.95 (t, 2H), 5.19 (bs, 2H), 5.65 (bs, 2H), 6.39 (s, 1H), 6.82 (s, 1H), 11.99 (bs, 1H). 13 C-NMR (100MHz, DMSO-d 6 ): ? 155.2, 151.8, 140.4, 132.9, 126.2, 125.8, 111.1, 96.9, 32.9, 31.1, 15.1. Formula: C 11 H 14 N 4 OS. MS (M+H): 251.0. HRMS: found (251.0966), calc (251.0963). IR: 3321.4 cm -1 (bs), 3219.2 cm -1 (bs), 2920.2 cm -1 , 2879.7 cm -1 , 1643.4 cm -1 , 1510.3 cm -1 , 1402.3 cm -1 , 1273.0 cm -1 . UV: 391.0nm (bs). mp: >300 o C. Preparation of symmetric salqu ligands (7). (Table 2, Chapter 2) To 1.0 equivalent (0.1 mmol) of the diamino 2-quinoxalinol intermediate (6) dissolved in 4 mL methanol, a solution of 10.0 equivalents (1.0 mmol) salicylaldehyde derivatives (18a-e) in 6 mL methanol was added. These two were combined with stirring, and after heating to reflux temperature for 1 hour, the reaction mixture becomes deep yellow or dark. After continued heating at reflux temperature for 48 hours, the product forms and precipitates as either dark yellow or red solids. The precipitate is filtered directly and washed with 95% ethanol and ice cold acetone 5 times each to obtain 105 symmetric salqu ligands as final products. Yields of the final products range from 40.0% to 80.0% with the purity of them ranging from 90.0% to 99.0%. All of the final products (except 7aa, 7ca and 7db) were identified and characterized by 1 H-NMR, 13 C-NMR, MS, HRMS, UV-Vis and IR. For the synthesis of 7aa, 7ca and 7db, 1.0 equivalent (0.1 mmol) of diamino 2- quinoxalinols (6) was dissolved into 4 mL methanol and 10.0 equivalents (1.0 mmol) salicylaldehyde derivates (18) were dissolved into 2 mL methanol. With stirring, the reaction solution becomes red after heating to reflux temperature for 40 minutes. After this, the solution was aloowed to continue to heat at reflux temperature for 48 hours. At this time, there were found to be a lot of red precipitates. Filter directly and wash with 95% ethanol and ice cold acetone 5 times each. Yields of these ranged from 50.0-60.0%. 7aa 1 H-NMR (400 MHz DMSO-d 6 ): ? 4.14 (s, 2H), 6.77-7.34 (m, 12H), 7.87 (s, 1H), 8.83 (s, 1H), 9.04 (s, 1H), 9.22 (bs, 1H, D 2 O exchangeable), 9.41 (bs, 1H, D 2 O exchangeable), 12.18 (bs, 1H, D 2 O exchangeable), 12.53 (bs, 1H, D 2 O exchangeable), 12.99 (bs, 1H, D 2 O exchangeable). 13 C-NMR (100MHz, DMSO-d 6 ): ? 165.6, 164.8, 160.7, 154.9, 150.0, 149.7, 146.2, 146.1, 145.7, 138.2, 137.9, 132.1, 129.7, 128.8, 126.9, 123.4, 122.9, 120.3, 120.2, 119.8, 119.6, 118.4, 106.0, 40.0. Formula: C 29 H 22 N 4 O 5 . MS: 507.0. HRMS: found (507.1666), calc (507.1668). IR: 3392.8 cm -1 (bs), 3005.2 cm -1 , 1656.8 cm -1 , 1616.3 cm -1 , 1467.8 cm -1 , 1271.1 cm -1 , 1234.4 cm -1 . UV: 383.0nm (bs). mp: 251.0 o C (Color changed). 106 7ab 1 H-NMR (400 MHz DMSO-d 6 ): ? 4.14 (s, 2H), 6.74-7.35 (m, 12H), 7.87 (s, 1H), 8.74 (s, 1H), 8.97 (s, 1H), 9.08 (bs, 1H, D 2 O exchangeable), 9.12 (bs, 1H, D 2 O exchangeable), 11.43 (bs, 1H, D 2 O exchangeable), 12.31 (bs, 1H, D 2 O exchangeable), 12.50 (bs, 1H, D 2 O exchangeable). 13 C-NMR (100MHz, DMSO-d 6 ): ? 164.3, 163.8, 160.6, 155.0, 153.8, 153.5, 150.2, 150.0, 146.5, 138.0, 137.9, 132.1, 131.1, 129.7, 128.9, 126.9, 122.4, 121.7, 120.2, 119.9, 118.1, 117.9, 117.7, 117.5, 116.5, 105.9, 40.0. Formula: C 29 H 22 N 4 O 5. MS (M+H): 507.0. HRMS: found (507.1667), calc (507.1668). IR: 3387.0 cm -1 (bs), 3005.0 cm -1 , 1662.6 cm -1 , 1616.4 cm -1 , 1573.9 cm -1 , 1487.1 cm -1 , 1282.7 cm -1 , 1153.4 cm -1 . UV: 378.0nm (bs). mp: 246.0 o C (Color changed). 7ac 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.31 (s, 9H), 1.34 (s, 9H), 4.15 (s, 2H), 6.77-7.44 (m, 12H), 7.62 (s, 1H), 8.58 (s, 1H), 8.70 (s, 1H), 12.26 (bs, 1H), 13.42 (bs, 1H), 13.60 (bs, 1H). 13 C-NMR (100MHz, DMSO-d 6 ): ? 165.4, 163.7, 160.6, 160.4, 155.1, 144.6, 138.4, 137.7, 137.4, 137.0, 133.9, 131.9, 131.7, 130.7, 129.3, 128.2, 126.4, 126.1, 119.2, 118.9, 118.7, 118.2, 117.9, 105.5, 34.7, 29.2. Formula: C 37 H 38 N 4 O 3. MS (M+H): 587.0. HRMS: found (587.3028), calc (587.3022). IR: 3437.2 cm -1 (bs), 3417.9 cm -1 (bs), 2953.0 cm -1 , 2912.5 cm -1 , 1672.3 cm -1 , 1606.7 cm -1 , 1500.6 cm -1 , 1431.2 cm -1 , 1394.5 cm -1 , 1197.8 cm -1 , 1143.8 cm -1 . UV: 285.7nm (bs), 387.9nm (bs). mp: 271.0-273.5 o C. 7ad 1 H-NMR (250 MHz DMSO-d 6 and CDCl 3 ): ? 1.23 (s, 18H), 1.32 (s, 9H), 1.34 (s, 9H), 4.14 (s, 2H), 7.01 (s, 1H), 7.12-7.41 (m, 9H), 7.59 (s, 1H), 8.58 (s,1H), 8.68 (s, 1H), 12.22 (bs, 1H), 13.25 (bs, 1H), 13.36 (bs, 1H). 13 C-NMR (62.5MHz, DMSO-d 6 and CDCl 3 ): ? 165.9, 164.3, 160.2, 158.6, 158.3, 155.3, 144.9, 140.6, 140.5, 138.9, 137.2, 107 137.1, 136.9, 131.7, 131.5, 129.5, 128.7, 128.4, 128.2, 127.2, 127.0, 126.5, 118.4, 118.1, 118.1, 105.6, 35.1, 34.1, 31.5, 29.4. Formula: C 45 H 54 N 4 O 3. MS (M+H): 699.0. HRMS: found (699.4276), calc (699.4274). IR: 3435.2 cm -1 (bs), 3415.9 cm -1 (bs), 2956.9 cm -1 , 2910.6 cm -1 , 2873.9 cm -1 , 1656.9 cm -1 , 1612.5 cm -1 , 1529.6 cm -1 , 1477.5 cm -1 , 1442.8 cm -1 , 1261.5 cm -1 , 1168.9 cm -1 . UV: 299.1nm (bs), 390.9nm (bs). mp: 279.1-280.1 o C. 7ae 1 H-NMR (400 MHz DMSO-d 6 ): ? 4.17 (s, 2H), 6.95-7.03 (m, 2H), 7.11 (s, 1H), 7.25-7.49 (m, 7H), 7.66 (d, 1H), 7.79 (d, 1H), 7.94 (s, 1H), 8.90 (s, 1H), 9.13 (s, 1H), 12.28 (bs, 1H), 12.57 (bs, 1H), 13.13 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 164.6, 164.0, 160.9, 160.8, 160.6, 155.0, 146.0, 138.1,137.9, 134.5, 133.8, 133.1, 132.3, 132.2, 131.2, 129.8, 128.9, 126.9, 120.2, 120.0, 119.9, 119.6, 118.1, 117.2, 117.1, 105.8, 40.0. Formula: C 29 H 22 N 4 O 3. MS (M+H): 475.0. HRMS: found (475.1762), calc (475.1770). IR: 3448.7 cm -1 (bs), 3427.5 cm -1 (bs), 3055.2 cm -1 , 3030.2 cm -1 , 1654.9 cm -1 , 1610.6 cm -1 , 1570.1 cm -1 , 1481.3 cm -1 , 1276.9 cm -1 , 1197.8 cm -1 . UV: 305.6nm (bs, ? = 3.2?10 4 ), 335.9nm, 390.5nm (bs, ? = 3.2?10 4 ). mp: 264.1-266.1 o C. 7ba 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.26 (d, J=6.8Hz, 6H), 3.50 (sept, 1H), 6.80 (t, 1H), 6.84 (t, 1H), 6.94 (d,1H), 6.99 (d, 1H), 7.01 (s, 1H), 7.14 (d, 1H), 7.22 (d, 1H), 7.92 (s, 1H), 8.87 (s, 1H), 9.11 (s, 1H), 9.24 (bs, 1H), 9.43 (bs, 1H), 12.24 (bs, 1H), 12.48 (bs, 1H), 13.06 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 166.0, 165.6, 164.8, 154.6, 150.0, 149.7, 146.2, 146.1, 145.4, 138.1, 131.8, 131.1, 123.5, 122.9, 120.3, 120.2, 120.0, 119.6, 119.2, 118.3, 106.0, 30.4, 20.6. Formula: C 25 H 22 N 4 O 5. MS (M+H): 459.0. HRMS: found (459.1675), calc (459.1668). IR: 3421.7 cm -1 (bs), 3059.1 cm -1 , 2966.5 cm - 108 1 , 2926.0 cm -1 , 1656.9 cm -1 , 1616.4 cm -1 , 1556.6 cm -1 , 1465.9 cm -1 , 1373.3 cm -1 , 1273.0 cm -1 , 1230.6 cm -1 . UV: 306.5nm (bs), 389.6nm (bs). mp: >300 o C. 7bb 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.23 (d, J=6.8Hz, 6H), 3.48 (sept, 1H), 6.74-7.12 (m, 7H), 7.88 (s, 1H), 8.74 (s, 1H), 9.01 (s,1H), 9.08 (bs, 1H, D 2 O exchangeable), 9.13 (bs, 1H, D 2 O exchangeable), 11.46 (bs, 1H, D 2 O exchangeable), 12.36 (bs, 1H, D 2 O exchangeable), 12.42 (bs, 1H, D 2 O exchangeable). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 165.9, 164.3, 163.8, 154.6, 153.8, 153.5, 150.2, 150.0, 146.2, 138.2, 131.8, 130.9, 122.3, 121.7, 120.2, 120.0, 118.0, 117.9, 117.6, 116.5, 105.8, 30.4, 20.6. Formula: C 25 H 22 N 4 O 5. MS (M+H): 458.0. HRMS: found (459.1665), calc (459.1668). IR: 3400.5 cm -1 (bs), 2962.7 cm -1 , 2926.0 cm -1 , 1656.9 cm -1 , 1627.9 cm -1 , 1579.7 cm -1 , 1490.8 cm -1 , 1400.0 cm -1 , 1273.0 cm -1 , 1219.0 cm -1 . UV: 299.1nm (bs), 387.0nm (bs). mp: 221.5 o C (Color changed). 7bc 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.27 (d, J=6.8Hz, 6H), 1.37 (s, 9H), 1.42 (s, 9H), 3.52 (sept, 1H), 6.93 (t, 1H), 6.95 (t, 1H), 7.20 (s, 1H), 7.38 (d, 1H), 7.44 (d, 1H), 7.54-7.58 (t, 2H), 8.00 (s, 1H), 8.94 (s, 1H), 9.19 (s,1H), 12.51 (bs, 1H), 13.73 (bs, 1H), 14.04 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 167.1, 166.3, 165.5, 160.5, 160.4, 154.6, 144.5, 137.9, 137.6, 137.1, 137.0, 132.2, 132.0, 131.4, 131.3, 130.8, 119.7, 119.4, 119.1, 118.9, 118.3, 105.9, 34.9, 30.4, 29.7, 20.6. Formula: C 33 H 38 N 4 O 3. MS (M+H): 539.0. HRMS: found (539.3024), calc (539.3022). IR: 3429.4 cm -1 (bs), 2956.9 cm -1 , 2872.0 cm -1 , 1660.7 cm -1 , 1606.7 cm -1 , 1467.8 cm -1 , 1431.2 cm -1 , 1388.8 cm -1 , 1270.0 cm -1 , 1199.7 cm -1 . UV: 302.2nm (bs), 386.2nm (bs). mp: 285.1-286.1 o C. 109 7bd 1 H-NMR (400 MHz DMSO-d 6 and CDCl 3 ): ? 1.20 (s, 9H), 1.21 (s, 9H), 1.21 (d, J=6.8Hz, 6H), 1.29 (s, 9H), 1.32 (s, 9H), 3.52 (sept, 1H), 6.99 (s, 1H), 7.17 (s, 2H), 7.34 (s, 1H), 7.37 (s, 1H), 7.62 (s, 1H), 8.59 (s, 1H), 8.72 (s, 1H), 12.12 (bs, 1H), 13.28 (bs, 1H), 13.39 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 and CDCl 3 ): 165.9, 165.7, 164.1, 158.5, 158.3, 155.1, 144.5, 140.5, 140.4, 138.8, 137.1, 136.9, 131.5, 131.2, 128.6, 128.1, 127.1, 126.8, 118.3, 118.1, 118.0, 105.4, 35.0, 34.1, 31.4, 30.3, 29.3, 20.1. Formula: C 41 H 54 N 4 O 3. MS (M+H): 651.0. HRMS: found (651.4274), calc (651.4268). IR: 3423.7 cm -1 (bs), 2958.8 cm -1 , 2910.6 cm -1 , 2870.1 cm -1 , 1653.0 cm -1 , 1614.4 cm -1 , 1581.6 cm -1 , 1469.8 cm -1 , 1437.0 cm -1 , 1390.7 cm -1 , 1363.7 cm -1 , 1253.7 cm -1 , 1203.6 cm -1 . UV: 299.6nm (bs), 387.9nm (bs). mp: 280.0-281.0 o C. 7be 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.23 (d, J=6.8Hz, 6H), 3.47 (sept, 1H), 6.91-7.00 (m, 4H), 7.08 (s, 1H), 7.39 (t, 1H), 7.44 (t, 1H), 7.66 (d, 1H), 7.76 (d, 1H), 7.93 (s, 1H), 8.87 (s, 1H), 9.15 (s, 1H), 12.28 (bs, 1H), 12.46 (bs, 1H), 13.14 (bs, 1H). 13 C- NMR (100 MHz, DMSO-d 6 ): ? 166.1, 164.6, 163.9, 160.9, 160.6, 154.6, 145.7, 137.9, 134.4, 133.8, 133.1, 132.4, 132.0, 131.1, 120.2, 119.8, 119.5, 118.1, 117.2, 117.1, 105.7, 30.4, 20.6. Formula: C 25 H 22 N 4 O 3. MS (M+H): 427.0. HRMS: found (427.1764), calc (427.1770). IR: 3441.0 cm -1 (bs), 2964.6 cm -1 , 2924.1 cm -1 , 1658.8 cm -1 , 1616.4 cm -1 , 1570.1 cm -1 , 1479.4 cm -1 , 1452.0 cm -1 , 1278.8 cm -1 , 1203.6 cm -1 . UV: 335.9nm (bs), 387.9nm (bs). mp: 288.5-289.3 o C. 110 7ca 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.23 (d, J=6.6Hz, 6H), 2.27 (m, 1H), 2.71 (d, J=7.0, 2H), 6.80 (t, 1H), 6.83 (t, 1H), 6.95 (d, 1H), 7.00 (d, 1H), 7.09 (s, 1H), 7.14 (t, 2H), 7.22 (t, 2H), 7.92 (s, 1H), 8.87 (s, 1H), 9.08 (s, 1H), 9.24 (bs, 1H, D 2 O exchangeable), 9.42 (bs, 1H, D 2 O exchangeable), 12.25 (bs, 1H, D 2 O exchangeable), 12.47 (bs, 1H, D 2 O exchangeable), 13.04 (bs, 1H, D 2 O exchangeable). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 165.6, 164.7,161.7, 155.2, 150.0, 149.7, 146.2, 146.1, 145.4, 138.1, 131.9, 131.2, 123.4, 122.9, 120.3, 120.2, 120.0, 119.6, 119.2, 118.3, 106.0, 42.1, 26.6, 23.1. Formula: C 26 H 24 N 4 O 5. MS (M+H): 473.0. HRMS: found (473.1818), calc (473.1825). IR: 3419.8 cm -1 (bs), 2949.2 cm -1 , 2866.2 cm -1 , 1656.9 cm -1 , 1618.3 cm -1 , 1579.7 cm -1 , 1465.9 cm -1 , 1373.3 cm -1 , 1271.1 cm -1 , 1232.5 cm -1 . UV: 301.3nm (bs), 381.0nm (bs). mp: 260.0-261.5 o C. 7cb 1 H-NMR (400 MHz DMSO-d 6 ): ? 0.98 (d, J=6.6Hz, 6H), 2.27 (m, 1H), 2.71 (d, J=7.0, 2H), 6.77-6.91 (m, 4H), 7.06 (s, 2H), 7.14 (s, 1H), 7.92 (s, 1H), 8.77 (s, 1H), 9.01 (s, 1H), 9.12 (bs, 1H), 9.15 (bs, 1H), 11.49 (bs, 1H,), 12.36 (bs, 1H), 12.45 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 164.4, 163.7, 161.5, 155.2, 153.8, 153.5, 150.2, 150.0, 146.2, 138.2, 131.9, 131.1, 120.2, 119.9, 117.9, 117.6, 117.5, 116.5, 105.8, 42.1, 26.7, 23.1. Formula: C 26 H 24 N 4 O 5. MS (M+H): 473.0. HRMS: found (473.1832), calc (473.1825). IR: 3427.5 cm -1 (bs), 3412.1 cm -1 (bs), 2956.9 cm -1 , 2924.1 cm -1 , 1658.8 cm -1 , 1618.3 cm -1 , 1577.8 cm -1 , 1483.3 cm -1 , 1379.1 cm -1 , 1286.5 cm -1 , 1213.2 cm -1 . UV: 303.9nm (bs), 395.7nm (bs). mp: 290.5 o C (Color changed). 111 7cc 1 H-NMR (400 MHz DMSO-d 6 ): ? 0.99 (d, J=6.6Hz, 6H), 13.7 (s, 9H), 1.42 (s, 9H), 2.29 (m, 1H), 2.72 (d, J=7.0, 2H), 6.93 (t, 1H), 6.95 (t, 1H), 7.20 (s, 1H), 7.38 (d, 1H), 7.44 (d, 1H), 7.53-7.58 (m, 2H), 8.01 (s, 1H), 8.93 (s, 1H), 9.16 (s, 1H), 12.51 (bs, 1H), 13.73 (bs, 1H), 14.03 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 167.1, 165.5, 161.9, 160.5, 160.4, 155.2, 144.5, 137.9, 137.2, 137.0, 132.2, 132.0, 131.9, 131.4, 130.8, 119.7, 119.4, 119.1, 118.9, 118.2, 105.9, 42.1, 34.9, 29.7, 26.6, 23.1. Formula: C 34 H 40 N 4 O 3. MS (M+H): 553.0. HRMS: found (553.3177), calc (553.3178). IR: 3423.7 cm -1 (bs), 2955.0 cm -1 , 2918.3 cm -1 , 2870.1 cm -1 , 1662.6 cm -1 , 1604.8 cm -1 , 1573.9 cm -1 , 1496.8 cm -1 , 1469.8 cm -1 , 1431.2 cm -1 , 1396.5 cm -1 , 1273.0 cm -1 , 1199.7 cm -1 . UV: 299.6nm (bs), 382.7nm (bs). mp: 285.1-286.7 o C. 7cd 1 H-NMR (250 MHz DMSO-d 6 and CDCl 3 ): ? 0.82 (d, J=6.6Hz, 6H), 1.10 (s, 9H), 1.11 (s, 9H), 1.19 (s, 9H), 1.22 (s, 9H), 2.13 (m, 1H), 2.57 (d, J=7.1, 2H), 6.88 (s, 1H), 7.04-7.06 (dd, 2H), 7.21 (d, 2H), 7.23 (d, 2H), 7.47 (s, 1H), 8.47 (s, 1H), 8.58 (s, 1H), 12.08 (bs, 1H), 13.15 (bs, 1H), 13.25 (bs, 1H). 13 C-NMR (62.5 MHz, DMSO-d 6 and CDCl 3 ): ? 166.6, 164.1, 161.4, 158.4, 158.1, 155.6, 144.4, 140.4, 138.7, 136.9, 136.8, 131.3, 128.5, 128.0, 127.0, 126.8, 118.2, 118.0, 117.8, 105.4, 42.0, 34.9, 34.0, 31.3, 29.3, 26.5, 22.6. Formula: C 42 H 56 N 4 O 3. MS (M+H): 665.0. HRMS: found (665.4431), calc (665.4430). IR: 3423.7 cm -1 (bs), 2956.9 cm -1 , 2920.1 cm -1 , 2880.1 cm -1 , 1656.9 cm -1 , 1616.4 cm -1 , 1583.6 cm -1 , 1469.8 cm -1 , 1437.0 cm -1 , 1386.8 cm -1 , 1367.5 cm -1 , 1255.7 cm -1 , 1207.4 cm -1 . UV: 301.3nm (bs), 389.6nm (bs). mp: 287.8-288.8 o C. 112 7ce 1 H-NMR (250 MHz DMSO-d 6 ): ? 0.98 (d, J=6.5Hz, 6H), 2.27 (m, 1H), 2.70 (d, J=6.9, 2H), 6.94-7.11 (m, 4H), 7.38 (s, 1H), 7.41-7.46 (m, 2H), 7.68 (d, 1H), 7.79 (d, 1H), 7.96 (s, 1H), 8.89 (s, 1H), 9.14 (s, 1H), 12.34 (bs, 2H), 13.14 (bs, 1H). 13 C-NMR (62.5 MHz, DMSO-d 6 ): ? 164.6, 163.9, 161.7, 160.9, 160.6, 155.2, 145.6, 138.0, 134.4, 133.8, 133.1, 132.4, 132.0, 131.2, 120.2, 120.0, 119.8, 119.5, 118.0, 117.2, 105.8, 42.1, 26.6, 23.1. Formula: C 26 H 24 N 4 O 3. MS (M+H): 441.0. HRMS: found (441.1922), calc (441.1926). IR: 3441.0 cm -1 (bs), 3425.6 cm -1 (bs), 2955.0 cm -1 , 2922.2 cm -1 , 2864.3 cm -1 , 1658.8 cm -1 , 1616.4 cm -1 , 1572.0 cm -1 , 1485.2 cm -1 , 1384.9 cm -1 , 1278.8 cm -1 , 1203.6 cm -1 . UV: 383.6nm (bs). mp: 286.5-288.5 o C. 7da 1 H-NMR (400 MHz DMSO-d 6 ): ? 2.14 (s, 3H), 2.95 (t, 2H), 3.13 (t, 2H), 6.81 (t, 1H), 6.84 (t, 1H), 6.95 (d, 1H), 7.00 (d, 1H), 7.11 (s, 1H), 7.15 (d, 1H), 7.23 (d, 1H), 7.92 (s, 1H), 8.88 (s, 1H), 9.08 (s, 1H), 9.25 (bs, 1H, D 2 O exchangeable), 9.43 (bs, 1H, D 2 O exchangeable), 12.23 (bs, 1H, D 2 O exchangeable), 12.53 (bs, 1H, D 2 O exchangeable), 13.02 (bs, 1H, D 2 O exchangeable). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 165.7, 164.8, 160.6, 155.0, 149.9, 149.7, 146.2, 146.1, 145.6, 138.2, 132.0, 131.1,123.4, 122.9, 120.3, 120.2, 120.0, 119.6, 119.2, 118.3, 106.1, 33.2, 30.5, 15.0. Formula: C 25 H 22 N 4 O 5 S . MS (M+H): 491.0. HRMS: found (491.1389), calc (491.1389). IR: 3415.9 cm -1 (bs), 2920.2 cm -1 , 2852.7 cm -1 , 1656.9 cm -1 , 1616.4 cm -1 , 1467.8 cm -1 , 1373.3 cm -1 , 1271.1 cm -1 , 1230.6 cm -1 . UV: 307.4nm (bs), 390.5nm (bs). mp: >300 o C. 7db 1 H-NMR (400 MHz DMSO-d 6 ): ? 2.14 (s, 3H), 2.94 (t, 2H), 3.12 (t, 2H), 6.77-6.93 (m, 4H), 7.06 (s, 2H), 7.14 (s, 1H), 7.92 (s, 1H), 8.78 (s, 1H), 8.80 (s, 1H), 9.12 113 (bs, 1H), 9.16 (bs, 1H), 11.48 (bs, 1H), 12.34 (bs, 1H), 12.49 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 164.4, 163.8, 153.8, 153.5, 150.2, 150.0, 132.0, 121.7, 120.2, 119.9, 118.1, 117.9, 117.7, 116.5, 105.9, 33.1, 30.1, 15.2. Formula: C 25 H 22 N 4 O 5 S . MS (M+H): 491.0. HRMS: found (491.1384), calc (491.1389). IR: 3439.1 cm -1 (bs), 2972.3 cm -1 , 2924.1 cm -1 , 1654.9 cm -1 , 1624.1 cm -1 , 1575.8 cm -1 , 1477.5 cm -1 , 1388.8 cm -1 , 1282.7 cm -1 , 1220.9 cm -1 . UV: 302.2nm (wbs), 391.4nm (bs). mp: >300 o C. 7dc 1 H-NMR (250 MHz DMSO-d 6 ): ? 1.36 (s, 9H), 1.40 (s, 9H), 2.14 (s, 3H), 2.94 (t, 2H), 3.11 (t, 2H), 6.93-6.98 (m, 2H), 7.20 (s, 1H), 7.39 (d, 1H), 7.41 (d, 1H), 7.54 (t, 2H), 8.00 (s, 1H), 8.93 (s, 1H), 9.14 (s, 1H), 12.56 (bs, 1H), 13.72 (bs, 1H), 14.01 (bs, 1H). 13 C-NMR (62.5 MHz, DMSO-d 6 ): ? 166.9, 165.2, 160.6, 160.4, 154.9, 144.6, 138.1, 137.2, 137.0, 132.1, 131.8, 131.3, 130.6, 119.6, 119.3, 118.9, 118.7, 118.2, 105.9, 34.9, 33.2, 30.5, 29.6, 15.3. Formula: C 33 H 38 N 4 O 3 S . MS (M+H): 571.0. HRMS: found (571.2738), calc (571.2743). IR: 3433.3 cm -1 (bs), 3417.9 cm -1 (bs), 2953.0 cm -1 , 2920.2 cm -1 , 2872.0 cm -1 , 1666.5 cm -1 , 1654.9 cm -1 , 1606.7 cm -1 , 1489.1 cm -1 , 1427.3 cm -1 , 1388.8 cm -1 , 1311.6 cm -1 , 1267.2 cm -1 . UV: 305.6nm (bs), 389.6nm (bs). mp: 262.0 o C (Color changed). 7dd 1 H-NMR (400 MHz DMSO-d 6 and CDCl 3 ): ? 1.20 (s, 9H), 1.21 (s, 9H), 1.29 (s, 9H), 1.32 (s, 9H), 2.15 (s, 3H), 2.90 (t, 2H), 3.12 (t, 2H), 6.97 (s, 1H), 7.14 (s, 2H), 7.31 (d, 1H), 7.34 (d, 1H), 7.56 (s, 1H), 8.55 (s, 1H), 8.65 (s, 1H), 12.20 (bs, 1H), 13.21 (bs, 1H), 13.32 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 and CDCl 3 ): ? 165.8, 164.3, 159.8, 158.6, 158.3, 155.4, 144.9, 140.5, 140.4, 139.0, 137.1, 137.0, 131.4, 131.3, 128.7, 114 128.2, 127.1, 126.9, 118.3, 118.1, 118.0, 105.6, 35.0, 34.1, 33.1, 31.4, 30.6, 29.3, 15.5. Formula: C 41 H 54 N 4 O 3 S . MS (M+H): 683.0. HRMS: found (683.4005), calc (683.3995). IR: 3441.0 cm -1 (bs), 3425.6 cm -1 (bs), 2956.9 cm -1 , 2914.4 cm -1 , 2870.1 cm -1 , 1656.9 cm -1 , 1616.4 cm -1 , 1583.6 cm -1 , 1469.8 cm -1 , 1433.1 cm -1 , 1386.8 cm -1 , 1269.2 cm -1 , 1259.5 cm -1 . UV: 302.2nm (bs), 391.4nm (bs). mp: 286.0-287.5 o C. 7de 1 H-NMR (400 MHz DMSO-d 6 ): ? 2.14 (s, 3H), 2.95 (t, 2H), 3.13 (t, 2H), 6.95- 7.04 (m, 4H), 7.12 (s, 1H), 7.42 (t, 1H), 7.47 (t, 1H), 7.70 (d, 1H), 7.79 (d, 1H), 7.96 (s, 1H), 8.91 (s, 1H), 9.14 (s, 1H), 12.30 (bs, 1H), 12.54 (bs, 1H), 13.12 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 164.7, 164.0, 160.9, 160.6, 155.0, 145.8, 138.1, 134.5, 133.8, 133.1, 120.2, 120.0, 119.9, 118.1, 117.2, 117.1, 105.8, 33.2, 30.5, 15.2. Formula: C 25 H 22 N 4 O 3 S . MS (M+H): 459.0. HRMS: found (459.1489), calc (459.1491). IR: 3441.0 cm -1 (bs), 3423.6 cm -1 (bs), 2916.4 cm -1 , 2841.2 cm -1 , 2796.8 cm -1 , 1660.7 cm -1 , 1614.4 cm -1 , 1570.1 cm -1 , 1479.4 cm -1 , 1398.4 cm -1 , 1276.9 cm -1 , 1201.6 cm -1 . UV: 335.9nm (bs), 387.0nm (bs). mp: 270.5 o C. Synthesis of intermediate 9ax, 2-quinoxalinol imines. (Table 4, Chapter 3) The synthesis of 2-quinoxalinol imine (9ax) begins with the addition of 1.0 equivalent of intermediates (6, 0.1mmol) dissolved in 4 mL methanol to a solution of 1.2 equivalents substituted salicylaldehyde derivatives (18, 0.12mmol) in 6 mL methanol. The two are combined with stirring for 14 hours. This is monitored by TLC. Once the diamino 2-quinoxalinol (6) starting material can no longer be seen by TLC, the reaction is considered complete. Pure 2-quinoxalinol imines (9a) are obtained by purification 115 using flash column chromatography with a solution of hexane : ethyl acetate, 3:1 as eluent. For sample (9ai), a modified procedure was used. The product begins to form as a red solid (9ai) after heating at reflux temperature for 4 hours. The red solid was filtered off and washed with 95% ethanol followed by ice cold acetone to obtain pure final 2- quinoxalinol imines (9ai). The one step yields of these range from 60.0-90.0%. 9aa 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.44 (s, 9H), 4.04 (s, 2H), 5.84 (bs, 2H), 6.59 (s, 1H), 6.80 (s, 1H), 6.59-7.74 (m, 9H), 8.98 (s, 1H), 12.15 (bs, 1H), 13.58 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 167.4, 164.0, 159.8, 155.5, 154.2 145.6, 138.8, 136.8, 133.4, 132.3, 132.2, 132.0, 131.8, 130.4, 129.5, 129.2, 128.7, 126.6, 125.0, 120.0, 119.0, 117.1, 97.7, 40.0, 35.0, 30.0. Formula: C 26 H 26 N 4 O 2 . MS (M+H): 426.0. HRMS: found (426.2051), calc (426.2056). IR: 3470.0 cm -1 (bs), 3375.4cm -1 (bs), 3182.6 cm -1 , 2956.9 cm -1 , 2927.9 cm -1 , 2870.1 cm -1 , 1728.2 cm -1 , 1656.9 cm -1 , 1624.1 cm -1 , 1271.1 cm -1 . mp: 196.0-199.0 o C. 9ab 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.20 (d, J=6.8, 6H), 1.44 (s, 9H), 3.61 (sept, 1H), 5.77 (bs, 2H), 6.60 (s, 1H), 6.94 (t, 1H), 7.38 (d, 1H), 7.53 (d, 1H), 7.55 (s, 1H), 9.03 (s, 1H), 12.07 (bs, 1H), 13.64 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 170.8, 163.8, 159.8, 159.6, 155.1, 145.3, 136.8, 133.1, 132.1, 131.8, 130.4, 124.8, 120.1, 119.0, 117.7, 97.8, 35.0, 29.9, 20.8, 14.6. Formula: C 22 H 26 N 4 O 2 . MS (M+H): 378.0. HRMS: found (378.2052), calc (378.2056). IR: 3442.9 cm -1 (bs), 3402.4 cm -1 (bs), 2958.8 cm -1 , 2872.0 cm -1 , 1710.9 cm -1 , 1651.1 cm -1 , 1626.0 cm -1 , 1502.6 cm -1 , 1234.4 cm -1 . mp: 250.0- 253.0 o C (Color changed). 116 9ac 1 H-NMR (250 MHz DMSO-d 6 ): ? 0.93 (d, J=6.6, 6H), 1.43 (s, 9H), 2.19 (m, 1H), 2.58 (d, 2H), 5.77 (bs, 2H), 6.59 (s, 1H), 6.93 (t, 1H), 7.37(d, 1H), 7.52 (d, 1H), 7.55 (s, 1H), 8.99 (s, 1H), 12.06 (bs, 1H), 13.62 (bs, 1H). 13 C-NMR (62.5 MHz, DMSO-d 6 ): ? 163.8, 159.8, 155.8, 155.2, 145.3, 136.8, 133.2, 132.1, 131.7, 130.4, 125.0, 120.3, 119.0, 117.6, 97.8, 41.7, 34.9, 29.7, 26.8, 23.1. Formula: C 23 H 28 N 4 O 2 . MS (M+H): 392.0. HRMS: found (392.2206), calc (392.2212). IR: 3392.8 cm -1 (bs), 2954.9 cm -1 , 2924.1 cm - 1 , 2866.2 cm -1 , 1710.0 cm -1 , 1626.0 cm -1 , 1600.9 cm -1 , 1371.4 cm -1 , 1232.5 cm -1 . mp: >300.0 o C. 9ad 1 H-NMR (250 MHz DMSO-d 6 ): ? 1.43 (s, 9H), 2.09 (s, 3H), 2.86 (t, 2H), 2.97 (t, 2H), 5.82 (bs, 2H), 6.59 (s, 1H), 6.93 (t, 1H), 7.37 (d, 1H) 7.51 (d, 1H), 7.53 (s, 1H), 12.11 (bs, 1H), 13.59 (bs, 1H). 13 C-NMR (62.5 MHz, DMSO-d 6 ): ? 163.9, 159.8, 155.5, 153.9, 145.5, 136.8, 133.3, 132.3, 131.8, 130.4, 125.0, 120.0, 119.0, 117.6, 97.8, 34.9, 32.8, 30.9, 29.7, 15.2. Formula: C 22 H 26 N 4 O 2 S. MS (M+H): 410.0. HRMS: found (410.1767), calc (410.1776). IR: 3469.9 cm -1 (bs), 3334.9 cm -1 (bs), 2920.2 cm -1 , 2954.9 cm -1 , 2918.3 cm -1 , 2875.9 cm -1 , 1710.8 cm -1 , 1662.6 cm -1 , 1626.0 cm -1 , 1429.3 cm -1 , 1234.4 cm -1 . mp: 225.0-227.0 o C. 9ae 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.31 (s, 9H), 1.44 (s, 9H), 4.05 (s, 2H), 5.81 (bs, 2H, D 2 O exchangeable), 6.58 (s, 1H), 7.20-7.55 (m, 8H), 8.99 (s, 1H), 12.15 (bs, 1H, D 2 O exchangeable), 13.32 (bs, 1H, D 2 O exchangeable). 13 C-NMR (100MHz, DMSO-d 6 ): ? 168.2, 162.4, 160.5, 159.5, 145.7, 142.7, 141.4, 137.7, 137.5, 134.1, 133.0, 117 132.8, 131.8, 131.0, 130.6, 123.4, 121.8, 102.9, 40.0, 39.8, 38.9, 36.2, 34.2. Formula: C 30 H 34 N 4 O 2 . MS: 482.0. HRMS: found (482.2681), calc (482.2682). IR: 3491.2 cm -1 (bs), 3375.4 cm -1 , 2955.08 cm -1 , 2870.18 cm -1 , 2821.98 cm -1 , 1718.68 cm -1 , 1653.0 cm -1 , 1626.0 cm -1 , 1502.6 cm -1 , 1238.0 cm -1 . mp: 248.0-250.0 o C. 9ae 15 N: 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.31 (s, 9H), 1.44 (s, 9H), 4.04 (s, 2H), 5.81 (bs, 2H, D 2 O exchangeable), 6.58 (s, 1H), 7.21-7.55 (m, 8H), 8.98 (d, 1H), 12.14 (bs, 1H, D 2 O exchangeable), 13.32 (bs, 1H, D 2 O exchangeable). 9af 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.18 (d, 6H), 1.26 (s, 9H), 1.28 (s, 9H), 4.00 (sept, 1H), 5.67 (bs, 2H), 6.59 (s, 1H), 7.40 (s, 1H), 7.54 (s, 1H), 7.58 (s, 1H), 9.04 (s, 1H), 12.06 (bs, 1H), 13.36 (bs, 1H). 13 C-NMR (100MHz, DMSO-d 6 ): ? 164.3, 159.6, 157.5, 155.1, 145.2, 140.7, 136.0, 133.0, 132.3, 128.2, 127.4, 124.8, 119.4, 117.6, 97.7, 35.1, 34.4, 31.8, 29.8, 20.8, 14.6. Formula: C 26 H 34 N 4 O 2. MS (M+H): 434. HRMS: found (434.2675), calc (434.2682). IR: 3489.2 cm -1 (bs), 3387.0 cm -1 , 2958.88 cm -1 , 2910.68 cm -1 , 2870.18 cm -1 , 2819.98 cm -1 , 1739.88 cm -1 , 1651.1 cm -1 , 1620.2 cm -1 , 1502.6 cm -1 , 1240.1 cm -1 . mp: 275.0-276.0 o C (Color changed). 9ag 1 H-NMR (400 MHz DMSO-d 6 ): ? 0.94 (d, 6H), 1.32 (s, 9H), 1.44 (s, 9H), 2.20 (m, 1H), 2.59 (d, 2H), 5.76 (bs, 2H), 6.59 (s, 1H), 7.40 (s, 1H), 7.54 (s, 1H), 7.57 (s, 1H), 9.01 (s, 1H), 12.06 (bs, 1H), 13.36 (bs, 1H). 13 C-NMR (100MHz, DMSO-d 6 ): ? 164.4, 157.5, 155.8, 155.0, 145.3, 140.7, 136.0, 133.0, 132.4, 128.2, 127.5, 125.0, 119.4, 117.6, 97.7, 41.7, 35.1, 34.4, 31.8, 29.8, 26.7, 23.1. Formula: C 27 H 36 N 4 O 2. MS (M+H): 448.0. HRMS: found (448.2839), calc (448.2838). IR: 3489.2 cm -1 (bs), 3400.5 cm -1 (bs), 118 2955.0 cm -1 , 2866.2 cm -1 , 2818.0 cm -1 , 1653.0 cm -1 , 1626.0 cm -1 , 1500.6 cm -1 , 1234.4 cm -1 . mp: >300.0 o C. 9ah 1 H-NMR (250 MHz DMSO-d 6 ): ? 1.31 (s, 9H), 1.44 (s, 9H), 2.11 (s, 2H), 2.83 (t, 2H), 2.96 (t, 2H), 5.80 (bs, 2H), 6.59 (s, 1H), 7.40 (s, 1H), 7.56 (s, 1H), 7.70 (s, 1H), 8.99 (s, 1H), 12.12 (bs, 1H), 13.33 (bs, 1H). 13 C-NMR (62.5MHz, DMSO-d 6 ): ? 164.5, 157.5, 155.5, 153.8, 145.4, 140.7, 136.1, 133.2, 132.5, 128.2, 127.5, 125.0, 119.4, 117.6, 97.6, 35.1, 34.4, 32.8, 31.8, 30.8, 29.8, 15.2. Formula: C 26 H 34 N 4 O 2 S . MS (M+H): 467. HRMS: found (467.2475), calc (467.2480). IR: 3473.8 cm -1 (bs), 3333.0 cm -1 (bs), 2956.8 cm -1 , 2912.5 cm -1 , 2870.1 cm -1 , 1711.08 cm -1 , 1662.6 cm -1 , 1626.0 cm -1 , 1500.6 cm -1 , 1234.5 cm -1 . mp: 239.5-240.5 o C. 9ai 1 H-NMR (400 MHz DMSO-d 6 ): ? 4.04 (s, 2H), 5.87 (bs, 2H, D 2 O exchangeable), 6.57 (s, 1H), 6.78-7.34 (m, 8H), 7.49 (s, 1H), 8.94 (s, 1H), 9.26 (bs, 1H, D 2 O exchangeable), 12.13 (bs, 1H, D 2 O exchangeable), 12.47 (bs, 1H, D 2 O exchangeable). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 162.6, 155.5, 154.0, 149.0, 146.0, 145.8, 138.8, 133.4, 132.8, 129.5, 128.7, 126.6, 124.9, 122.9, 120.8, 119.3, 119.2, 117.4, 97.5, 39.0. Formula: C 22 H 18 N 4 O 3. MS (M+H): 387.0. HRMS: found (387.1452), calc (387.1457). IR: 3489.2 cm -1 (bs), 3429.4 cm -1 (bs), 3394.7 cm -1 (bs), 2941.4 cm -1 , 2877.8 cm -1 , 2818.0 cm -1 , 1656.8 cm -1 , 1626.0 cm -1 , 1500.6 cm -1 , 1465.9 cm -1 , 1275.0 cm -1 , 1236.4 cm -1 . mp: 260.0-261.0 o C. 119 9aj-1 1 H-NMR (400 MHz CDCl 3 and DMSO-d 6 ): ? 1.40 (s, 9H), 1.41(s, 9H), 3.87(s, 2H), 4.04(t, 1H), 6.37-7.50 (m, 8H), 8.78 (s, 1H), 8.84 (s, 1H), 10.49 (bs, 1H), 14.09 (bs, 1H), 14.16 (bs, 1H). 13 C-NMR (100 MHz, CDCl 3 and DMSO-d 6 ): ? 166.0, 163.8, 161.2, 160.3, 160.0, 137.9, 137.0, 136.9, 135.7, 132.6, 131.6, 131.2, 130.0, 126.7, 119.7, 118.8, 105.5, 103.7, 60.2, 34.9, 29.7. Formula: C 30 H 34 N 4 O 3. MS (M): 498.3. HRMS: found (498.2628), calc (498.2631). IR: 3386.9 cm -1 (bs), 2955.8 cm -1 , 2877.8 cm - 1 , 2818.0 cm -1 , 1680.2 cm -1 , 1609.6 cm -1 , 1519.4 cm -1 , 1430.6 cm -1 , 1303.4 cm -1 , 1143.5 cm -1 . mp: 255.0-256.0 o C (Color changed). 9ak-1 1 H-NMR (400 MHz CDCl 3 and DMSO-d 6 ): ? 1.35 (s, 18H), 1.47 (s, 18H), 4.10 (s, 2H), 4.11 (t, 3H), 6.60 (s, 1H), 6.79 (s, 1H), 7.20-7.47 (m, 4H), 8.63 (s, 1H), 8.67 (s, 1H), 9.38 (bs, 1H), 13.55 (bs, 1H), 13.64 (bs, 1H). 13 C-NMR (100 MHz, CDCl 3 and DMSO-d 6 ): ? 169.7, 163.2, 146.4, 145.3, 141.7, 133.1, 132.0, 123.1, 39.8, 38.9, 36.3, 34.2. Formula: C 38 H 50 N 4 O 3. MS (M): 610.4. HRMS: found (610.3883), calc (610.3891). IR: 3489.2 cm -1 (bs), 3379.4 cm -1 (bs), 3232.1 cm -1 (bs), 2957.0 cm -1 , 2871.0 cm -1 , 2869.0 cm -1 , 1709.1 cm -1 , 1686.0 cm -1 , 1614.6 cm -1 , 1515.0 cm -1 , 1297.5 cm -1 , 1250.5 cm -1 . mp: 250.0-251.0 o C (Color Changed). Preparation of asymmetric salqu ligands (8). (Table 5, Chapter 3) This procedure is the same as that for preparing the 2-quinoxalinol imine (9ax); however, when diamino 2-quinoxalinol (6) can no longer be observed using TLC, a second 5 equivalents of the salicylaldehyde derivative 18? (0.5mmol) can be added directly to the reaction mixture. The mixture was then allowed to heat at reflux 120 temperature for an additional 14 hours. This was found to result in a large quantity of precipitates. These precipitates were isolated by filtering, and then washed with 95% ethanol and ice cold acetone 5 times each. The pure products, asymmetric salqu ligands (8), were identified and characterized by NMR, IR, MS and HRMS. Two step yields of these range from 40.0-70.0%. 8a 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.31 (s, 9H), 1.36 (s, 9H), 1.42 (s, 9H), 4.18 (s, 2H) 6.90-7.56 (m, 11H), 7.97 (s, 1H), 8.94 (s, 1H), 9.13 (s, 1H), 13.49 (bs, 1H, D 2 O exchangeable), 14.01 (bs, 1H, D 2 O exchangeable) 13 C-NMR (100 MHz, DMSO-d 6 ): ? 167.1, 164.9, 160.4, 158.4, 145.0, 140.7, 138.2, 137.8, 137.2, 136.7, 131.7, 130.6, 129.6, 128.6, 128.1, 126.7, 119.6, 118.6, 118.3, 35.1, 34.9, 34.3, 31.7, 29.7, 29.6, 25.7. Formula: C 41 H 46 N 4 O 3. MS (M + ): 642.0. HRMS: found (642.3559), calc (642.3570). IR: 3437.2 cm - 1 (bs), 3423.7 cm -1 (bs), 2955.4 cm -1 , 2910.6 cm -1 , 2870.1 cm -1 , 1658.8 cm -1 , 1610.6 cm -1 , 1577.8 cm -1 , 1431.2.9 cm -1 , 1392.6.0 cm -1 , 1195.9 cm -1 , 1168.9 cm -1 . mp: 251.0-253.0 o C. 8b 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.38 (s, 9H), 4.17 (s, 2H), 6.88-7.88 (m, 13H), 7.96 (s, 1H), 8.90 (s, 1H), 9.11 (s, 1H), 12.12 (bs, 2H), 14.46 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 164.7, 164.2, 160.8, 160.5, 155.0, 146.2, 137.9, 137.3, 137.1, 134.4, 132.2, 132.0, 131.7, 131.1, 130.6, 129.7, 128.9, 126.9, 120.5, 119.7, 119.6, 118.7, 118.0, 117.0, 105.7. Formula: C 33 H 30 N 4 O 3. MS (M + ): 387.0. HRMS: found (530.2320), calc (530.2318). IR: 3425.6 cm -1 (bs), 3147.8 cm -1 (bs), 3394.7 cm -1 (bs), 2920.2 cm -1 , 2864.3 cm -1 , 2785.2 cm -1 , 1660.7 cm -1 , 1608.6 cm -1 , 1483.3 cm -1 , 1384.9 cm -1 , 1201.7 cm -1 , 1147.7 cm -1 . mp: 239.0-241.0 o C. 121 8c 1 H-NMR (400 MHz CDCl 3 and DMSO-d 6 ): ? 1.30 (s, 9H), 1.37 (s, 9H), 1.40 (s, 9H) 4.17 (s, 2H), 6.89-7.89 (m, 11H), 7.91 (s, 1H), 8.86 (s, 1H), 9.07 (s, 1H), 12.53 (bs, 1H), 13.65 (bs, 1H), 13.68 (bs, 1H). 13 C-NMR (100 MHz, CDCl 3 and DMSO-d 6 ): ? 166.8, 166.7, 165.7, 160.7, 160.6, 160.4, 158.1, 154.9, 151.7, 144.6, 140.5, 138.4, 137.7, 137.2, 137.0, 136.3, 132.1, 131.8, 131.5, 131.2, 129.6, 128.7, 128.1, 127.9, 126.7, 119.6, 119.3, 118.9, 118.3, 105.9, 35.0, 34.9, 34.3, 31.9, 31.7, 29.6. Formula: C 41 H 46 N 4 O 3. MS (M + ): 642.0. HRMS: found (642.3583), calc (642.3570). IR: 3373.5 cm -1 (bs), 2956.9 cm -1 , 2924.1 cm -1 , 2866.2 cm -1 , 1654.9 cm -1 , 1602.9 cm -1 , 1275.0 cm -1 , 1488.8 cm -1 , 1203.9 cm -1 , 1174.7 cm -1 . mp: 260.0-262.0 o C. 8d 1 H-NMR (400 MHz CDCl 3 and DMSO-d 6 ): ? 1.17 (s, 9H), 1.25 (s, 9H), 1.29 (s, 9H), 2.04 (s, 3H), 2.87 (t, 2H), 3.08 (t, 2H), 6.70-7.54 (m, 7H), 8.52 (s, 1H), 8.61 (s, 1H), 12.13 (bs, 1H), 13.15 (bs, 1H), 13.50 (bs, 1H). 13 C-NMR (100 MHz, CDCl 3 and DMSO-d 6 ): ? 165.8, 165.5, 164.2, 160.7, 159.9, 159.8, 158.5, 158.2, 155.3, 144.9, 144.6, 140.5, 140.4, 138.9, 138.6, 137.7, 137.0, 136.9, 131.5, 131.4, 131.2, 130.8, 128.7, 128.1, 127.0, 126.8, 118.8, 118.2, 105.6, 35.0, 34.8, 34.1, 33.1, 30.6, 29.3, 29.2, 15.4. Formula: C 37 H 46 N 4 O 3 S . MS (M + ): 626.0. HRMS: found (626.3279), calc (626.3291). IR: 3421.7 cm -1 (bs), 2953.0 cm -1 (bs), 2914.4 cm -1 (bs), 2862.4 cm -1 , 1656.9 cm -1 , 1610.6 cm -1 , 1577.8 cm -1 , 1431.2 cm -1 , 1313.5 cm -1 , 1267.2 cm -1 . mp: 244.0-245.0 o C (Color changed). 8e 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.38 (s, 9H), 2.15 (s, 3H), 2.94 (t, 2H), 3.13 (t, 2H), 6.89-7.99 (m, 9H), 8.92 (s, 1H), 9.13 (s, 1H), 11.99 (bs, 1H), 12.49 (bs, 1H), 122 14.47 (bs, 1H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 164.6, 164.1, 160.8, 160.5, 154.8, 146.0, 137.3, 137.1, 134.4, 132.1, 132.0, 131.7, 131.0, 130.6, 120.5, 119.7, 119.6, 118.7, 118.0, 117.0, 105.7, 34.9, 33.2, 30.5, 29.6, 15.2. Formula: C 29 H 30 N 4 O 3 S . MS (M + ): 514.0. HRMS: found (514.2039), calc (514.2039). IR: 3419.8 cm -1 (bs), 2914.4 cm -1 , 2864.3 cm - 1 , 2787.1 cm -1 , 1658.8 cm -1 , 1608.6 cm -1 , 1483.3 cm -1 , 1392.6 cm -1 , 1207.4 cm -1 , 1143.8 cm -1 . mp: 229.0-230.0 o C (Color changed). 8f 1 H-NMR (400 MHz CDCl 3 and DMSO-d 6 ): ? 0.92 (s, 9H), 1.01 (s, 9H), 1.04 (s, 9H), 1.80 (s, 3H), 2.62 (t, 2H), 2.82 (t, 2H), 6.46-7.31 (m, 7H), 8.28 (s, 1H), 8.40 (s, 1H). 13 C-NMR (100 MHz, CDCl 3 and DMSO-d 6 ): ? 170.4, 170.3, 169.1, 168.6, 165.5, 165.3, 164.9, 163.0, 149.4, 149.3, 145.3, 143.7, 143.4, 142.5, 141.7, 138.9, 136.9, 136.4, 136.2, 135.9, 135.5, 135.3, 133.0, 131.8, 123.9, 123.7, 123.1, 122.7, 39.6, 39.0, 38.0, 37.9, 36.2, 35.4, 34.1, 34.0, 20.2. Formula: C 37 H 46 N 4 O 3 S . MS (M + ): 626.0. HRMS: found (626.3277), calc (626.3291). IR: 3466.1 cm -1 (bs), 3329.1 cm -1 (bs), 2955.0 cm -1 , 2899.0 cm -1 , 2873.9 cm -1 , 1662.6 cm -1 , 1618.3 cm -1 , 1492.9.6 cm -1 , 1427.3 cm -1 , 1236.4 cm -1 , 1205.5 cm -1 , 1172.7 cm -1 . mp: 240.0-241.0olor changed). 8g 1 H-NMR (400 MHz CDCl 3 and DMSO-d 6 ): ? 0.92 (d, 6H), 1.22 (s, 9H), 1.30 (s, 9H), 1.32 (s, 9H), 2.24 (m, 1H), 2.69 (d, 2H), 6.74-7.58 (m, 7H), 8.58 (s, 1H), 8.66 (s, 1H). 13.23 (bs, 1H), 13.41(bs, 1H), 13.56 (bs, 1H). 13 C-NMR (100 MHz, CDCl 3 and DMSO-d 6 ): ? 165.0, 164.0, 163.0, 160.5, 158.6, 155.7, 144.7, 144.5, 140.5, 138.6, 137.7, 137.6, 137.1, 131.4, 131.1, 130.9, 130.7, 130.5, 128.7, 127.1, 119.1, 118.9, 118.3, 118.1, 117.8, 105.6, 42.1, 35.0, 34.8, 34.1, 31.4, 29.4, 29.3, 26.7, 22.7. Formula: C 38 H 48 N 4 O 3. 123 MS (M + ): 608.0. HRMS: found (608.3730), calc (608.3726). IR: 3421.7 cm -1 (bs), 2955.0 cm -1 (bs), 2910.6 cm -1 (bs), 2872.0 cm -1 , 1662.6 cm -1 , 1606.7 cm -1 , 1492.9 cm -1 , 1425.4 cm -1 , 1317.4 cm -1 , 1276.9 cm -1 , 1134.1 cm -1 , 1089.8 cm -1 . mp: 260.0-261.0 o C (Color changed). 8h 1 H-NMR (250 MHz DMSO-d 6 ): ? 0.98 (d, 6H), 1.37 (s, 9H), 2.27 (m, 1H), 2.70 (d, 2H), 6.86-7.98 (m, 9H), 8.90 (s, 1H), 9.12 (s, 1H). 12.36 (bs, 1H), 14.01(bs, 1H), 14.48 (bs, 1H). 13 C-NMR (62.5 MHz, DMSO-d 6 ): ? 164.5, 164.1, 161.9, 161.6, 160.8, 160.5, 155.2, 145.8, 144.5, 137.9, 137.2, 137.1, 137.0, 134.3, 132.2, 132.0, 131.6, 131.4, 131.1, 130.7, 130.6, 120.5, 119.7, 119.6, 119.4, 119.1, 118.9, 118.6, 118.1, 117.9, 117.0, 105.8, 42.1, 34.9, 29.7, 26.6, 23.1. Formula: C 20 H 32 N 4 O 3. MS (M + ): 496.0. HRMS: found (496.2472), calc (496.2474). IR: 3435.2 cm -1 (bs), 3423.7 cm -1 (bs), 2953.0 cm -1 , 2916.4 cm -1 , 2868.2 cm -1 , 1656.9 cm -1 , 1610.6 cm -1 , 1473.6 cm -1 , 1431.2 cm -1 , 1392.6 cm -1 , 1276.8 cm -1 , 1193.9 cm -1 , 1143.8 cm -1 . mp: 271.0-273.0 o C (Color changed). 8i 1 H-NMR (400 MHz CDCl 3 and DMSO-d 6 ): ? 0.91 (d, 6H), 1.22 (s, 9H), 1.28 (s, 9H), 1.32 (s, 9H), 2.23 (m, 1H), 2.69 (d, 2H), 6.73-7.58 (m, 7H), 8.58 (s, 1H), 8.66 (s, 1H). 13.22 (bs, 1H), 13.41(bs, 1H), 13.56 (bs, 1H). 13 C-NMR (100 MHz, CDCl 3 and DMSO-d 6 ): ? 165.9, 165.2, 163.7, 161.8, 161.6, 160.7, 158.6, 155.7, 144.7, 144.4, 140.5, 138.6, 137.7, 137.6, 137.1, 131.4, 131.1, 131.0, 130.9, 130.7, 130.5, 128.7, 127.1, 119.1, 118.9, 118.3, 118.1, 117.7, 105.5, 42.1, 35.0, 34.8, 34.7, 31.4, 29.3, 29.2, 26.8, 22.7. Formula: C 38 H 48 N 4 O 3. MS (M + ): 608.0. HRMS: found (608.3721), calc (608.3726). IR: 124 3500.0 cm -1 (bs), 2955.0 cm -1 (bs), 2912.5 cm -1 (bs), 2872.0 cm -1 , 1662.6 cm -1 , 1604.8 cm -1 , 1492.9 cm -1 , 1431.2 cm -1 , 1356.6 cm -1 , 1207.4 cm -1 , 1138.0 cm -1 . mp: 264.0-266.0 o C. 8j 1 H-NMR (400 MHz CDCl 3 and DMSO-d 6 ): ? 1.21 (d, 6H), 1.30 (s, 9H), 1.33 (s, 9H), 1.34 (s, 9H), 3.49 (m, 1H), 6.74-7.61 (m, 7H), 8.57 (s, 1H), 8.68 (s, 1H). 12.05 (bs, 1H), 13.22 (bs, 1H), 13.58 (bs, 1H). 13 C-NMR (100 MHz, CDCl 3 and DMSO-d 6 ): ? 165.4, 163.5, 160.7, 160.5, 158.6, 158.1, 155.1, 144.7, 144.4, 140.5, 138.5, 137.8, 137.6, 137.1, 131.5, 131.3, 131.0, 130.9, 130.7, 130.4, 128.7, 127.1, 119.1, 118.9, 118.3, 118.2, 118.1, 117.9, 105.4, 35.0, 34.8, 34.1, 31.4, 30.3, 29.4, 29.3, 20.2. Formula: C 37 H 46 N 4 O 3. MS (M + ): 594.0. HRMS: found (594.3566), calc (594.3570). IR: 3415.9 cm -1 (bs), 3138.2 cm -1 (bs), 2955.0 cm -1 , 2872.0 cm -1 , 2792.9 cm -1 , 1664.6 cm -1 , 1606.7 cm -1 , 1489.1 cm -1 , 1479.4 cm -1 , 1211.3 cm -1 , 1184.3 cm -1 . mp: 269.0-271.0 o C. 8k 1 H-NMR (400 MHz CDCl 3 and DMSO-d 6 ): ? 1.27 (d, 6H), 1.38 (s, 9H), 3.51 (m, 1H), 6.89-7.99 (m, 9H), 8.91 (s, 1H), 9.16 (s, 1H). 12.06 (bs, 1H), 12.43 (bs, 1H), 14.52 (bs, 1H). 13 C-NMR (100 MHz, CDCl 3 and DMSO-d 6 ): ? 164.6, 164.1, 161.0, 160.9, 160.6, 160.5, 154.6, 145.9, 137.2, 137.1, 134.4, 133.1, 132.0, 131.7, 131.0, 130.6, 120.6, 120.1, 119.7, 119.6, 119.5, 118.7, 118.1, 117.9, 117.2, 117.0, 105.6, 34.9, 30.4, 29.6, 20.6. Formula: C 29 H 30 N 4 O 3. MS (M + ): 482.0. HRMS: found (482.2313), calc (482.2318). IR: 3448.7 cm -1 (bs), 3145.9 cm -1 (bs), 2958.8 cm -1 , 2870.1 cm -1 , 2794.9 cm -1 , 1658.8 cm -1 , 1610.6 cm -1 , 1481.3 cm -1 , 1384.9 cm -1 , 1207.4 cm -1 , 1147.7 cm -1 . mp: 265.0-267.0 o C. 125 8l 1 H-NMR (400 MHz CDCl 3 and DMSO-d 6 ): ? 1.19-1.30 (m, 33H), 3.47 (m, 1H), 6.72-7.59 (m, 7H), 8.57 (s, 1H), 8.67 (s, 1H). 12.02 (bs, 1H), 13.35 (bs, 1H), 13.43 (bs, 1H). 13 C-NMR (100 MHz, CDCl 3 and DMSO-d 6 ): ? 166.0, 165.4, 164.2, 160.7, 158.3, 155.0, 144.3, 140.4, 138.8, 137.7, 136.9, 131.5, 131.1, 131.0, 130.8, 128.1, 126.9, 118.9, 118.3, 118.2, 117.9, 105.5, 34.9, 34.7, 34.1, 31.3, 30.3, 29.3, 29.2, 20.1. Formula: C 37 H 46 N 4 O 3. MS (M + ): 594.0. HRMS: found (594.3572), calc (594.3570). IR: 3417.9 cm - 1 (bs), 3142.0 cm -1 (bs), 2956.9 cm -1 , 2877.8 cm -1 , 2868.2 cm -1 , 1656.9 cm -1 , 1606.7 cm -1 , 1469.8 cm -1 , 1433.1 cm -1 , 1209.4 cm -1 , 1172.7 cm -1 . mp: 258.0-260.0 o C. Preparation of symmetric salqus copper complexes 10xyCu. (Table 6, Chapter 4) To a 5mL DCM or DMF solution of symmetric salqu ligands (7, 0.05 mmol) (if salqu ligands contain tertbutyl group, DCM were used as solvent otherwise DMF as solvent), 5 mL MeOH and metal acetate (Cu(OAc) 2 ?H 2 O, 0.06 mmol, 11.98mg) was added and stirred at reflux temperature for two hours. The reaction solution changes to deep dark from bright yellow. The solution was concentrated and washed with 95% EtOH or ether to obtain 10xyCu with a yield of no less than 82.0%. 10adCu: IR: 3067, 2955, 1661, 1586, 1528, 1491, 1416, 1377, 1260, 1209, 1173, 1130 cm -1 . MS: 760.0 (M+H); HRMS: found (760.3413); calc (760.3422). UV-Vis (DCM): 286 nm (? = 6.13?10 4 ), 330.0 nm (? = 7.54?10 4 ), 458.0 nm (? = 9.14?10 4 ). DMSO: 280.0 nm (? = 3.4?10 4 ), 325.0 nm (? =2.8?10 4 ), and 454.0 nm (? =1.5?10 4 ). 126 10aeCu: MS: 536.1 (M+H); HRMS: found (536.0912); calc (536.0909). Preparation of symmetric salqus uranyl complexes 10xyU. (Table 7, Chapter 4) To a 5mL DCM or DMF solution of symmetric salqu ligands (7, 0.05 mmol), (if salqu ligands contain tertbutyl group, DCM were used as solvent otherwise DMF as solvent), 5 mL MeOH and uranyl acetate (UO 2 (OAc) 2 ?2H 2 O, 0.06 mmol, 25.5 mg) was added and stirred at room temperature for two hours. The reaction solution becomes deep red from bright yellow. The solution was concentrated and washed with 95% EtOH to obtain 10xyU with yield no less than 80.0%. 10aaU: 1 H-NMR (400 MHz DMSO-d 6 ): ? 4.22 (s, 2H), 6.54-8.67 (m, 13H), 9.55 (s, 1H), 9.71 (s, 1H), 11.77 (bs, 1H), 11.82 (bs, 1H), 12.69 (bs, 1H). IR: 3397 cm -1 , 3337 cm -1 , 2965 cm -1 , 1657 cm -1 , 1620 cm -1 , 1582 cm -1 , 1545 cm -1 , 1491 cm -1 , 1445 cm -1 , 1204 cm -1 , 903 cm -1 . MS: 816.2 (M+H+CH 3 CN); HRMS: found (816.2178); cal (816.2183). UV-Vis (DMF): 365.0 nm (? = 1.10?10 4 ), 450 nm. 10abU: MS: 816.0 (M+H); HRMS: found (816.2186); calc (816.218). 10adU: 1 H-NMR (400 MHz DMSO-d6): ? 1.19 (s, 18H), 1.64 (s, 18H), 4.11 (s, 2H), 7.09-7.63 (m, 10H), 7.70(s, 1H), 9.19 (s, 1H), 9.32 (s, 1H), 12.18 (bs, 1H). IR: 3433 cm -1 , 2957 cm -1 , 1655 cm -1 , 1620 cm -1 , 1383 cm -1 , 1283 cm -1 , 1229 cm -1 , 1153 cm -1 , 937 127 cm -1 , 760 cm -1 . MS: 967.4 (M+H); HRMS: found (967.4514); calc (967.4524). UV-Vis (DMSO): 295.0 nm (? = 2.5?10 4 ), 375.0 nm (? =1.6?10 4 ), and 440.0 nm (? =1.5?10 4 ). 10aeU: 1 H-NMR (400 MHz DMSO-d 6 ): ? 4.20 (s, 2H), 6.73-6.77 (t, 2H), 7.00- 7.04 (t, 2H), 7.24-7.88 (m, 10H), 8.12(s, 1H), 9.60 (s, 1H), 9.76 (s, 1H), 12.67 (bs, 1H). IR: 3397 cm -1 , 3337 cm -1 , 2965 cm -1 , 1657 cm -1 , 1620 cm -1 , 1582 cm -1 , 1545 cm -1 , 1491 cm -1 , 1445 cm -1 , 1204 cm -1 , 1144 cm -1 , 1040 cm -1 . MS: 784.0 (M+H+CH3CN); HRMS: found (784.2280); calc (784.2285 ). UV-vis (DMSO): 290 nm (? = 2.0?10 4 ), 370 nm (? = 1.5?10 4 ), 440nm (? = 1.5?10 4 ). 10bdU: 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.22 (d, 6H), 1.26 (s, 18H), 1.69 (s, 18H), 3.50 (m, 1H), 7.26-7.80 (m, 6H), 9.30 (s, 1H), 9.46 (s, 1H), 12.28 (bs, 1H). IR: 3444 cm -1 , 2958 cm -1 , 1710 cm -1 , 1666 cm -1 , 1587 cm -1 , 1423 cm -1 , 1371 cm -1 , 1224 cm -1 , 898 cm -1 . MS: 919.2 (M+H); HRMS: found (919.4514); calc (919.4524). 10beU: 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.28 (d, 6H), 3.56 (m, 1H), 6.74-8.17 (m, 10H), 9.61 (s, 1H), 9.81 (s, 1H), 12.58 (bs, 1H). IR: 3406 cm -1 , 2966 cm -1 , 1654 cm -1 , 1602 cm -1 , 1539 cm -1 , 1463 cm -1 , 1400 cm -1 , 1384 cm -1 , 1145 cm -1 , 898 cm -1 . MS: 736.2 (M+H); HRMS: found (736.2280); calc (736.2285). UV-Vis (DMF): 287nm (? = 1.7?104), 304nm (? = 1.6?104), 360nm (? = 1.3?10 4 ), 385nm (? = 1.3?10 4 ), 419nm (? = 1.4?10 4 ). 10cbU: MS: 782.2 (M+H+CH3CN); HRMS: 782.2343 (obs); 782.2340 (cal). 128 10ceU: 1 H-NMR (400 MHz DMSO-d 6 ): ? 1.00 (d, 6H), 2.28 (m, 1H), 2.74 (d, 2H), 6.75 (t, 2H), 7.03 (t, 2H), 7.44 (s, 1H), 7.65 (m, 2H), 7.87 (t, 2H), 8.19 (s, 1H), 9.61 (s, 1H), 9.78 (s, 1H), 12.54 (bs, 1H). IR: 3395 cm -1 , 2927 cm -1 , 1637 cm -1 , 1606 cm -1 , 1539 cm -1 , 1463 cm -1 , 1435 cm -1 , 1383 cm -1 , 1282 cm -1 , 937 cm -1 . MS: 709.2 (M+H); HRMS: found (709.2167); calc (709.2176). 10deU: 1 H-NMR (400 MHz DMSO-d 6 ): ? 2.15 (s, 3H), 2.96 (t, 2H), 3.16 (t, 2H), 6.75 (t, 2H), 7.03 (t, 2H), 7.46 (s, 1H), 7.66 (m, 2H), 7.87 (t, 2H), 8.19 (s, 1H), 9.62 (s, 1H), 9.78 (s, 1H), 12.64 (bs, 1H). IR: 3408 cm -1 , 1655 cm -1 , 1637 cm -1 , 1601 cm -1 , 1583 cm -1 , 1537 cm -1 , 1464 cm -1 , 1440 cm -1 , 1382 cm -1 , 1300 cm -1 , 1199 cm -1 , 1150 cm -1 , 897 cm -1 , 760 cm -1 . MS: 768.2 (M+H); HRMS: found (768.2013); calc (768.2006). 11bU: MS: 799.0 (M+H); HRMS: 799.2645 (obs); 709.2646 (cal). Preparation of symmetric salqus cobalt complexes (10xyCo). (Table 8, Chapter 4) To a 5mL DCM or DMF solution of symmetric salqu ligands (7, 0.05 mmol), (if salqu ligands contain tertbutyl group, DCM were used as solvent otherwise DMF as solvent), 5 mL MeOH and cobalt acetate (Co(OAc) 2 ?4H 2 O, 0.06 mmol, 14.95mg) was added and stirred at reflux temperature for two hours. The reaction solution becomes blood red from bright yellow. The solution was concentrated and washed with 95% EtOH or ether to obtain 10xyCo with yield no less than 80.0%. 129 10adCo: IR: 3066, 2957, 1665, 1614, 1572, 1524, 1501, 1462, 1410, 1256, 1180, 1128 cm -1 . MS: 755.3 (M+H); HRMS: found (755.3369); calc (755.3372). UV-Vis (DCM): 322.0 nm (? = 6.15?10 4 ), 437.0 nm (? = 7.08?10 4 ). Preparation of symmetric salqus manganese complexes (10xyMn). (Table 8, Chapter 4) To a 5mL DCM or DMF solution of symmetric salqu ligands (7, 0.05 mmol), (if salqu ligands contain tertbutyl group, DCM were used as solvent otherwise DMF as solvent), 5 mL MeOH and manganese acetate (Mn(OAc) 2 ?4H 2 O, 0.06 mmol, 14.71mg) was added and stirred at reflux temperature for two hours. The reaction solution becomes dark from bright yellow. The solution was concentrated and washed with 95% EtOH or ether to obtain 10xyMn with yield no less than 80.0%. 10adMn: IR: 3385, 3248, 3208, 2955, 2911, 1670, 1582, 1532, 1462, 1416, 1317, 1248, 1177, 1130 cm -1 . MS: 751.3 (M+H); HRMS: found (751.3420); calc (751.3429). UV-Vis (DCM): 372.0 nm (? = 4.06?10 4 ), 510.0 nm, (? = 7.13?10 4 ). 11bMn: MS: 583.0 (M+H); HRMS: 583.1531 (obs); 583.1542 (cal). 130 Preparation of symmetric salqus nickel complexes (10xyNi). (Table 8, Chapter 4) To a 5mL DCM or DMF solution of symmetric salqu ligands (7, 0.05 mmol), (if salqu ligands contain tertbutyl group, DCM were used as solvent otherwise DMF as solvent), 5 mL MeOH and nickel acetate (Ni(OAc) 2 ?4H 2 O, 0.06 mmol, 14.93mg) was added and stirred at reflux temperature for two hours. The reaction solution becomes red from bright yellow. The solution was concentrated and washed with 95% EtOH or ether to obtain 10xyNi with yield no less than 90.0%. 10adNi: IR: 3067, 2955, 2870, 1665, 1616, 1584, 1533, 1598, 1464, 1414, 1379, 1260, 1182, 1130 cm -1 . MS: 755.3 (M+H); HRMS: found (755.3461); calc 755.3471. UV-Vis (DCM): 268.0 nm (? = 4.66?10 4 ), 314.0 nm (? = 4.81?10 4 ), 388.0 nm (? = 5.78?10 4 ), 452.0 nm (? = 9.24?10 4 ). Preparation of symmetric salqus palladium complexes (10adPd, 10aePd). (Table 8, Chapter 4) To a 5mL DCM solution of symmetric salqu ligands (7ad, 0.05 mmol, 35.00mg), 5 mL MeOH and palladium acetate (Pd(OAc) 2 , 0.06 mmol, 13.47mg) was added and stirred at reflux temperature for two hours. The reaction solution becomes orange from bright yellow. Finally, there are a lot of orange solids that precipitate out. The solution was filtered and washed with ether to obtain 10adPd with 92.0% yield. To a 5mL DMF solution of symmetric salqu ligands (7ae, 0.05 mmol), 5 mL MeOH and palladium acetate (Pd(OAc) 2 , 0.06 mmol, 13.47mg) was added and stirred at 131 reflux temperature for two hours. The reaction solution becomes deep orange from bright yellow. Finally, there are a lot of orange solids that precipitate out. The solution was filtered and washed with 95% EtOH to obtain 10aePd with 86.0% yield. Preparation of symmetric salqus iron complexes (10aaFe, 10aeFe). (Table 8, Chapter 4) To a 5mL DMF solution of symmetric salqu ligands (7aa, 0.05 mmol, 25.33mg), 5 mL MeOH and ferrous chloride (FeCl 2 ?4H 2 O, 0.06 mmol, 11.93mg) was added and stirred at reflux temperature for two hours. The reaction solution becomes black from bright yellow. The solution was concentrated and washed with 95% EtOH to obtain 10aaFe with 95.0%. To a 5mL DMF solution of symmetric salqu ligands (7ae, 0.05 mmol, 23.73mg), 5 mL MeOH and ferrous chloride (FeCl 2 ?4H 2 O, 0.06 mmol, 11.93mg) was added and stirred at reflux temperature for two hours. The reaction solution becomes black from bright yellow. Finally, there are a lot of black solids that precipitate out. The solution was filtered and washed with 95% EtOH to obtain 10aeFe with 87.4%. Preparation of symmetric salqus magnesium complexes (10adMg, 10bdMg, 10ceMg). To a 5mL DCM solution of symmetric salqu ligands (7ad, 0.05 mmol, 35.00mg), 5 mL MeOH and magnesium acetate (Mg(OAc) 2 ?4H 2 O, 0.06 mmol, 12.87mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not 132 change. TLC show that the starting materials, symmetric salqu ligands 7ad, was still in the reaction solution. 7ad finally were separated to be proved by 1 HNMR. To a 5mL DCM solution of symmetric salqu ligands (7bd, 0.05 mmol, 32.55mg), 5 mL MeOH and magnesium acetate (Mg(OAc) 2 ?4H 2 O, 0.06 mmol, 12.87mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. TLC show that the starting materials, symmetric salqu ligands 7bd, was still in the reaction solution. To a 5mL DMF solution of symmetric salqu ligands (7ce, 0.05 mmol, 22.03mg), 5 mL MeOH and magnesium acetate (Mg(OAc) 2 ?4H 2 O, 0.06 mmol, 12.87mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. TLC show that the starting materials, symmetric salqu ligands 7ce, was still in the reaction solution. Preparation of symmetric salqus zinc complexes (10adZn, 10aeZn, 10daZn). To a 5mL DCM of symmetric salqu ligands (7ad, 0.05 mmol, 35.00mg), 5 mL MeOH and zinc acetate (Zn(OAc) 2 ?2H 2 O, 0.06 mmol, 13.64mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. TLC show that only starting materials, symmetric salqu ligands 7ad, was still in the reaction solution. 7ad finally were separated to be proved by 1 HNMR. To a 5mL DMF solution of symmetric salqu ligands (7ae, 0.05 mmol, 23.73mg), 5 mL MeOH and zinc acetate (Zn(OAc) 2 ?2H 2 O, 0.06 mmol, 13.64mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. 133 TLC show that only starting materials, symmetric salqu ligands 7ae, was still in the reaction solution. To a 5mL DMF solution of symmetric salqu ligands (7da, 0.05 mmol, 24.53mg), 5 mL MeOH and zinc acetate (Zn(OAc) 2 ?2H 2 O, 0.06 mmol, 13.64mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. TLC show that only starting materials, symmetric salqu ligands 7da, was still in the reaction solution. Preparation of symmetric salqus zinc complexes (10adZn). To a 5mL DCM solution of symmetric salqu ligands (7ad, 0.05 mmol, 35.00mg), 5 mL MeOH and zinc chloride (ZnCl 2 , 0.06 mmol, 8.18mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. TLC show that only starting materials, symmetric salqu ligands 7ad, was still in the reaction solution. 7ad finally were separated to be proved by 1 HNMR. Preparation of symmetric salqus gadolinium (III) complexes (10adGa, 10cbGa). To a 5mL DCM solution of symmetric salqu ligands (7ad, 0.05 mmol, 35.00mg), 5 mL MeOH and gadolinium (III) chloride hydrate (0.06 mmol, 15.82mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. TLC show that only starting materials, symmetric salqu ligands 7ad, was still in the reaction solution. 7ad finally were separated to be proved by 1 HNMR. 134 To a 5mL DMF solution of symmetric salqu ligands (7cb, 0.05 mmol, 23.63mg), 5 mL MeOH and gadolinium (III) chloride hydrate (0.06 mmol, 15.82mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. TLC show that only starting materials, symmetric salqu ligands 7cb, was still in the reaction solution. Preparation of symmetric salqus cerium complexes (10adCe, 10aeCe). To a 5mL DCM solution of symmetric salqu ligands (7ad, 0.05 mmol, 35.00mg), 5 mL MeOH and cerium (III) acetate hydrate (0.06 mmol, 19.04mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. TLC show that only starting materials, symmetric salqu ligands 7ad, was still in the reaction solution. 7ad finally were separated to be proved by 1 HNMR. To a 5mL DMF solution of symmetric salqu ligands (7ae, 0.05 mmol, 23.73mg), 5 mL MeOH and cerium (III) acetate hydrate (0.06 mmol, 19.04mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. TLC show that only starting materials, symmetric salqu ligands 7ae, was still in the reaction solution. Preparation of symmetric salqus cerium complexes (10adCe). To a 5mL DCM solution of symmetric salqu ligands (7ad, 0.05 mmol, 35.00mg), 5 mL MeOH and cerium (III) chloride hydrate (0.06 mmol, 15.82mg) was added and stirred at reflux temperature for 24 hours. The reaction solution color does not change. 135 TLC show that only starting materials, symmetric salqu ligands 7ad, still in the reaction solution. Crystal growth of salqu uranyl complexes 10aeU, 10aaU, 10beU and 10ceU. (Figure 12, 13 Chapter 4) Crystals of salqu uranyl complexes 10aeU, 10aaU, 10beU and 10ceU were obtained in good yield from slow diffusion of diethyl ether into a saturated dimethyl formamide solution of salqu uranyl complexes at room temperature for one or two weeks. (Crystallographic data for salqu uranyl complexes see Table 11, 12 Chapter 4) Crystal growth of salqu uranyl complexes 10adU and 10bdU. (Figure 12, 13 Chapter 4) Crystals of 10adU and 10bdU were grown by layering a saturated aqueous solution of uranyl acetate salt with a saturated acetone solution of salqu lignads 7ad and 7bd at room temperature for one or two weeks. (Crystallographic data for salqu uranyl complexes see Table 11, 12 Chapter 4) Preparation of solid phase salqu lignads 12-1 and 12-2. (Scheme 4, Chapter 5) To a DCM solution of (PS) aminomethyl resin (0.1mmol), add glutaric anhydride (0.5 mmol) at room temperature reacts for 24 hours. Beads were on ninhydrin test, negative result will indicate 100.0% loading. After acylation of amino of resins was completed, the resin was washed with DCM, DMF and MeOH three times each. These were dried under vacuum for 1 day. Resin PL can be further acylation with 0.15mol 136 ligand 7cd using 0.22 mmol 4-dimethyl-aminopyridine (DMAP) and 0.22 mmol N,N?- diisopropyl-carbodiimide (DIC) in the anhydrous DMF at room temperature for three days. Resins were then washed by DCM, DMF and MeOH three times each. Vacuum drying 1 day is needed for extraction test. IR of 12-1 and 12-2: 3381.2, 1658.8, 1622.3, 1577.8, 1489.1, 1278.8 cm -1 . Recovery of salqu Cu complexes 13-1Cu and 13-2Cu. (Scheme 4, Chapter 5) 20mg 13-1Cu and 13-2Cu resins were mixed with DCM/CH 3 COOH (2:1) 3ml, 10mg sodium triacetoxyborohydride was added to keep reacting for 4 hours. The maximum amount of Cu 2+ can be recovered (70.0%, determined by Atomic Absorption spectroscopy). Method 1: application of salqu complexes as catalysts. (Table 14, Chapter 6) The synthesis of products in table 14, chapter 6 begins with the mixture of catalyst 10adCu (0.02 mmol, 15.2mg), 2 mmol of starting materials (aryl methylene compounds) dissolved in 2 mL acetonitrile and 1mL tert-butylhydroperoxide decane solution (6 mmol). This solution was allowed to stir for 18 hours heated to 70 o C and monitored by TLC. Once starting material can no longer be seen by TLC, the reaction is considered complete. Pure products are obtained using flash column chromatography with a solution of hexane:ethyl acetate, 10-20:1 as eluent. The yields of final pure products are from 45.0-99.0%. 137 Method 2: application of salqu complexes as catalysts. (Table 14, Chapter 6) For lower yielding products, a somewhat modified procedure begins with of the addition of catalyst 10adCu (0.02mmol, 15.2mg) and 2.0mmol of starting materials (aryl methylene compounds) dissolved in 2.0mL acetonitrile and 1.0mL tert- butylhydroperoxide decane solution (6.0mmol). This reaction mixture is allowed to stir for 18 hours at 70 o C. After 18 hours, an additional 1.0mL tert-butylhydroperoxide decane solution (6.0mmol) is added and the solution is heated at reflux temperature for another 18 hours and monitored by TLC. Once the starting material can no longer be seen by TLC, the reaction is considered complete. Pure products are obtained by purification using flash column chromatography with a solution of hexane : ethyl acetate, 10-20:1 as eluent. The yields of final pure products are from 65.0-92.0%. 20 1 H-NMR (400 MHz, CDCl 3 ): ? 7.49 (t, 4H), 7.62 (t, 2H), 7.84 (d, 4H). 13 C- NMR (100 MHz, CDCl 3 ): ? 196.8, 137.6, 132.5, 130.1, 128.3. 22 N-benzylidenebenzylamine: 1 H-NMR (400 MHz, CDCl 3 ): ? 4.87 (s, 2H), 7.28- 7.93 (m, 10H), 8.43 (s, 1H). 13 C-NMR (100 MHz, CDCl 3 ): ? 162.5, 139.0, 136.4, 134.5, 130.9, 130.6, 64.9. Benzaldehyde: 1 H-NMR (400 MHz, CDCl 3 ): ? 7.50 (t, 2H), 7.60 (t, 1H), 7.86 (d, 2H), 10.01 (s, 1H). 13 C-NMR (100 MHz, CDCl 3 ): ? 191.9, 136.0, 134.0, 129.3, 128.6. 138 24 1 H-NMR (400 MHz, CDCl 3 ): ? 3.91 (s, 3H), 7.43 (t, 2H), 7.53 (t, 1H), 8.05 (d, 2H). 13 C-NMR (100 MHz, CDCl 3 ): ? 167.1, 132.9, 130.2, 129.6, 128.4, 128.2, 126.9, 52.0. 26 1 H-NMR (250 MHz, CDCl 3 ): ? 2.71 (s, 3H), 8.15 (d, 2H), 8.35 (d, 2H). 13 C- NMR (62.5 MHz, CDCl 3 ): ? 196.3, 141.4, 129.3, 123.9, 27.0. 28 1 H-NMR (400 MHz, CDCl 3 ): ? 1.43 (t, 3H), 4.60 (q, 2H), 7.53 (t, 2H), 7.67 (t, 1H), 8.01 (d, 2H). 13 C-NMR (100 MHz, CDCl 3 ): ? 186.5, 163.9, 134.9, 132.4, 130.0, 128.9, 62.4, 14.1. 30 1 H-NMR (400 MHz, CDCl 3 ): ? 1.02 (t, 3H), 1.97 (m, 2H), 2.96 (t, 2H), 7.46 (t, 2H), 7.53 (t, 1H), 7.96 (d, 2H). 13 C-NMR (100 MHz, CDCl 3 ): ? 200.4, 137.1, 132.9, 128.4, 128.2, 128.0, 40.5, 27.2, 13.9. 32 1 H-NMR (400 MHz, CDCl 3 ): ? 7.50 (t, 4H), 7.62 (t, 2H), 7.85 (d, 4H). 13 C- NMR (100 MHz, CDCl 3 ): ? 196.8, 137.6, 132.4, 130.1, 128.3. 34 1 H-NMR (400 MHz, CDCl 3 ): ? 2.57 (s, 3H), 7.49 (t, 2H), 7.60 (t, 1H), 7.94 (d, 2H). 13 C-NMR (100 MHz, CDCl 3 ): ? 198.4, 137.3, 133.6, 129.1, 128.6, 27.2. 36 1 H-NMR (400 MHz CDCl 3 ): ? 7.50 (t, 2H), 7.60 (t, 1H), 7.86 (d, 2H), 10.01 (s, 1H). 13 C-NMR (100 MHz, CDCl 3 ): ? 191.9, 136.0, 134.0, 129.3, 128.6. 139 39 1 H-NMR (400 MHz, DMSO-d 6 ): ? 7.02 (s, 2H), 7.80 (dd, 2H), 8.13 (dd, 2H). 13 C-NMR (100 MHz, DMSO-d 6 ): ? 185.1, 138.7, 134.0, 131.9, 126.5. 41 1 H-NMR (250 MHz, CDCl 3 ): ? 2.71 (s, 3H), 7.56 (m, 2H), 7.62 (m, 4H), 8.05 (s, 1H). 13 C-NMR (62.5 MHz, CDCl 3 ): ? 198.1, 135.6, 134.4, 132.5, 130.2, 129.6, 128.5, 128.4, 127.8, 126.8, 123.9. 53 1 H-NMR (400 MHz, CDCl 3 ): ? 7.57-7.96 (m, 5H), 8.54 (d, 1H), 9.27 (s, 2H). 13 C-NMR (100 MHz, CDCl 3 ): ? 152.5, 142.9, 135.8, 130.4, 127.6, 127.3, 126.5, 120.5. 55 1 H-NMR (400 MHz, CDCl 3 ): ? 7.29 (m, 1H), 7.47 (t, 1H), 7.63 (t, 1H), 7.73 (d, 1H), 8.06 (m, 2H), 8.60 (m, 1H). 13 C-NMR (100 MHz, CDCl 3 ): ? 150.3, 148.2, 136.0, 129.4, 128.2, 127.8, 126.5, 121.0. Calculation Section (Table 3, Chapter 3) Calculations were run using Gaussian 03 at Alabama super computer system. The density functional theory method B3LYP/6-31G(d) was used to characterize intermediates (6) and 2-quinoxalinol imines (9a) and ground states in vacuum using Gaussian 03. Calculations using B3LYP/6-31G(d) were used for geometry optimizations and the calculation of vibrational frequencies, which confirmed all stationary points as minima and provided thermodynamic corrections. The effect of methanol was 140 approximated by subsequent single-point calculations using the conductor-like polarizable continuum model (CPCM). The default Gaussian 03 dielectric constant of 32.63 was used for methanol. Partial charges for the intermediate (6) and 2-quinoxalinol imines (9a) were obtained using CHELPG method. Calculation data was shown onto the support information of The Journal of Organic Chemistry article. (Wu, X.; Gorden, A. E. V.; Tonks, S. A.; Vilseck, J. Z. J. Org. 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